Heterocyclic compound

ABSTRACT

The present invention provides a heterocyclic compound having a RORγt inhibitory action. 
     The present invention relates to a compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification.
 
or a salt thereof.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound having an RORγtinhibitory action, a medicament containing the compound, and the like.

BACKGROUND OF THE INVENTION

Th17 cell and inflammatory cytokine (IL-17A, IL-17F, etc.) producedthereby has been drawing attention, since they cause a decrease in QOLas a severe etiology cell and factor accompanying enhancement of asystemic new immune response, in various autoimmune disease such asinflammatory bowel disease (IBD), rheumatoid arthritis, multiplesclerosis or psoriasis.

However, the existing therapeutic drugs show only limited effects, andtherefore, the earliest possible development of a novel therapeutic drughas been desired.

Moreover, it has been recently clarified that a Retinoid-related OrphanReceptor (ROR) γt, which is one of the orphan nuclear receptors, playsan important role in the differentiation of Th17 cells and production ofIL-17A/IL-17F. That is, it has been reported that RORγt is mainlyexpressed in Th17 cells and functions as a transcription factor ofIL-17A and IL-17F, as well as a master regulator of Th17 celldifferentiation.

Therefore, a medicament that inhibits the action of RORγt is expected toshow a treatment effect on various immune disease by suppressingdifferentiation and activation of Th17 cells.

Patent Document 1 reports the following compound represented by thegeneral formula:

P-M-M₁

whereinM is a 3- to 8-membered linear chain consisting of carbon atoms, 0-3carbonyl groups, 0-1 thiocarbonyl group, and 0-4 heteroatoms selectedfrom O, N and S(O)_(p),one of P and M₁ is -G, and the other is -A-B;G is a group represented by the formula (IIa) or formula (IIb):

Ring D, including the two atoms of Ring E to which it is attached, is a5- or 6-membered ring consisting of carbon atoms and 0-3 heteroatomsselected from N, O and S(O)_(p); Ring D is substituted with 0-2 R or 0-2carbonyl, and there are 0-3 ring double bonds;Ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl andpyridazinyl, which is substituted with 1-3 R;A is selected from a C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and a 5-to 12-membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from N, O and S(O)_(p), and substituted with 0-2R⁴;B is X—Y—R^(4a) or the like;X is absent, —(cR²R^(2a)) or the like;Y is selected from a C₃₋₁₀ carboncycle and a 3- to 10-memberedheterocycle; andR^(4a) is a C₁₋₆ alkyl substituted with 0-2 R^(4c), or the like, whichhas a Xa factor inhibitory action, and is useful for the treatment ofthromboembolism.

Patent Document 2 discloses, as a fused heterocyclic compound, acompound represented by the formula:

whereinR^(1A) is an optionally substituted hydrocarbon group or an optionallysubstituted hydrocarbon-oxy group,R^(2A) and R^(3A) are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group or the like, orR^(2A) and R^(3A) in combination optionally form, together with thecarbon atoms which they are bonded to, an optionally substitutedhydrocarbon ring;R^(5A) is a hydrogen atom or a halogen atom,

Q′ is

-   -   wherein    -   [A¹] are the same or different and each is a methylene group        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by hydroxy group(s) and the like, wherein the two        substituents bonded to the single carbon atom are optionally        combined to each other to form a hydrocarbon ring, and    -   n is an integer of 1 to 5, or the like, and Ring B′ is a benzene        ring optionally further having substituent(s), or the like,        which has a RORγt inhibitory action, and is useful for the        treatment of inflammatory bowel disease (IBD) and the like.

Patent Document 3 discloses, as a heterocyclic compound, a compoundrepresented by the formula:

whereinRing A is an optionally substituted cyclic group,Q is a bond, an optionally substituted C₁₋₁₀ alkylene, an optionallysubstituted C₂₋₁₀ alkenylene or an optionally substituted C₂₋₁₀alkynylene,R¹ is a substituent,Ring B is a thiazole ring, an isothiazole ring or a dihydrothiazolering, each optionally further substituted in addition to R², andR² is an optionally substituted cyclyl-carbonyl-C₁₋₆ alkyl group, anoptionally substituted aminocarbonyl-C₁₋₅ alkyl group, an optionallysubstituted cyclyl-C₁₋₆ alkyl group, an optionally substitutedcyclyl-C₁₋₅ alkylamino-carbonyl group, an optionally substitutedaminocarbonyl-C₂₋₆ alkenyl group, an optionally substituted C₁₋₆alkylcarbonylamino-C₁₋₆ alkyl group, an optionally substitutedcyclyl-aminocarbonyl group, an optionally substituted cyclyl-carbonylgroup or an optionally substituted non-aromatic heterocyclic group,which has a RORγt inhibitory action, and is useful for the treatment ofinflammatory disease, autoimmune disease and the like.

Patent Document 4 discloses, as a heterocyclic compound, a compoundrepresented by the formula:

whereinRing A is a C₃₋₁₀ carbocycle;L is a group selected from a bond, —CHR¹⁰CHR¹⁰—, —CR¹⁰═CR¹⁰— and —C≡C—;R¹⁰ is H, halo, OH or C₁₋₄ alkyl;Q is selected from C, CH and N;---- is an optional bond; provided that when Q is N, then the optionalbond is absent;Ring B is a 5- to 6-membered heterocycle containing heteroatoms selectedfrom N, NR⁶, O and S(O)_(p), and substituted by 0-3 R⁵;optionally, Ring B is further fused with phenyl substituted with 0-2 R⁵or a 5- to 6-membered aromatic heterocycle containing 1 to 2 heteroatomsselected from N, NR⁶, O and S(O)_(p), and substituted with 0-2 R⁵;R¹ are each independently H, halo, C₁₋₂ alkyl, —O(C₁₋₄ alkyl), CN,—CH₂NH₂ or —C(═NH) NH₂;R² is H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₆ haloalkyl, 6haloalkoxy, CO(C₁₋₄ alkyl), CONH₂, CO₂H, and a 5- to 7-memberedheterocycle containing 1 to 4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O and S(O)_(p), and substituted with 1-2 R^(2a); and R³ is aC₁₋₆ alkyl group substituted with 1-3 R^(3a), a C₃₋₁₀ carboncyclesubstituted with 1-3 R³, or a 5- to 10-membered heterocycle containing 1to 4 heteroatoms selected from N, NR⁷, O and S(O)_(p), and substitutedwith 1-3 R^(1a),which is a Factor XIIa, and is useful for the treatment ofthromboembolism, inflammatory disease and the like.

Patent Document 5 discloses, as a heterocyclic compound, a compoundrepresented by the formula:

whereinA¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a substituent, or anitrogen atom,A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a substituent, or anitrogen atom,A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a substituent, or anitrogen atom, or,provided that when A² is CR^(A2) wherein R^(A2) is a substituent, and A³is CR^(A3) wherein R^(A3) is a substituent, then. R^(A2) and R^(A3) incombination optionally form, together with the carbon atoms which theyare bonded to, a carbocycle or a heterocycle, R¹ is 1) an optionallysubstituted carbocyclic group, 2) an optionally substituted monocyclicheterocyclic group (excluding an optionally substituted 2-oxo-3-azetidylgroup), 3) an optionally substituted fused heterocyclic group (excludingan optionally substituted 7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-ylgroup, an optionally substituted 8-oxo-1-azabicyclo[4.2.0]oct-2-en-7-ylgroup and an optionally substituted8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl group), or 4) anoptionally substituted spiro ring group,R² is a hydrogen atom or a substituent,one of R³ or R⁴ is an optionally substituted carbocyclic group, anoptionally substituted aromatic nitrogen-containing heterocyclic groupor an optionally substituted fused non-aromatic heterocyclic group, andthe other is a hydrogen atom or a substituent,R⁵ is a hydrogen atom or a substituent, andR⁹ is a hydrogen atom or a hydroxy group, provided that when R⁹ is ahydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and CR^(A3),respectivelywhich has a RORγt inhibitory action, and is useful for the treatment ofinflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn'sdisease (CD), rheumatoid arthritis, multiple sclerosis, psoriasis andthe like.

Patent Document 6 discloses, as a heterocyclic compound, a compoundrepresented by the formula:

whereinR¹ is C₁₋₂ alkyl, halogen or CF₃;R² is H, Cl, F or methyl;R³ is H, methyl;R⁴ is H, C₁₋₆ alkyl or benzyl optionally substituted by CF₃;R⁵ is methyl, nitro, halogen, CN, CF₃ or —C(O)OCH₂CH₃; R⁶ is Cl, F orCF₃; andm is 0 or 1,which is an androgen receptor modulator.

DOCUMENT LIST Patent Document [Patent Document 1] WO 2004/108892 [PatentDocument 2] WO 2013/042782 [Patent Document 3] WO 2013/018695 [PatentDocument 4] WO 2013/055984 [Patent Document 5] WO 2013/100027 [PatentDocument 6] WO 2008/121602 SUMMARY OF THE INVENTION Problems to beSolved by the Invention

The present invention aims to provide a compound having a superior RORγtinhibitory action, and useful as an agent for the prophylaxis ortreatment of psoriasis, inflammatory bowel disease (IBD), ulcerativecolitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiplesclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemiclupus erythematosus (SLE) and the like.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof has a superior RORγt inhibitoryaction based on the specific chemical structure thereof and affordssuperior efficacy as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like. The present inventors have conducted intensivestudies based on the finding and completed the present invention.

Accordingly, the present invention relates to the followings.

[1] A compound represented by the following formula (I):

wherein

Ring A is an optionally further substituted 6-membered aromatic ring;

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is an optionally substituted C₁₋₆ alkoxy-C₁₋₂ alkyl group, orR^(1a) is bonded to one substituent on Ring A to form an optionallysubstituted 5-membered hydrocarbon ring, wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A, or (2) a trimethylsilyl group;

R⁴ is an optionally substituted C₃₋₆ cycloalkyl group;

X is CR⁶ or N;

R⁵ is an optionally substituted C₁₋₆ alkyl group or an optionallysubstituted C₁₋₆ alkoxy group;

R⁶ is a hydrogen atom or a substituent; and

when X is CR⁶, R⁵ and R⁶ in combination optionally form Ring D, whereinRing D is an optionally substituted 5- or 6-membered oxygen-containingheterocycle containing 1 to 2 oxygen atoms as heteroatoms in addition tocarbon atoms, or a salt thereof (hereinafter sometimes to be referred toas compound (I)).

[1′] The compound or salt of the above-mentioned [1], wherein

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is an optionally substituted C₁₋₆ alkoxy-C₁₋₂ alkyl group, or(2) a trimethylsilyl group, orthe group represented by the formula:

is a group represented by the formula:

wherein

is a single bond or a double bond.[2] The compound or salt of the above-mentioned [1], wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms;

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group, or R^(1a) is bonded to onesubstituent on Ring A to form a 5-membered hydrocarbon ring, wherein theone substituent on Ring A is bonded to the position adjacent to thebonding position of R¹ on Ring A, or (2) a trimethylsilyl group;

R⁴ is a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group optionally substituted by            3- to 14-membered non-aromatic heterocyclic group(s)            optionally substituted by 1 to 3 substituents selected from            a C₁₋₆ alkyl group and an oxo group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group,    -   (3) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 3- to        14-membered non-aromatic heterocyclic group(s) optionally        substituted by 1 to 3 substituents selected from a C₁₋₆ alkyl        group and an oxo group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group;

X is CR⁶ or N;

R⁵ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 C₁₋₆ alkoxygroups, or(2) a C₁₋₆ alkoxy group;

R⁶ is a hydrogen atom; and

when X is CR⁶, R⁵ and R⁶ in combination optionally form Ring D, whereinRing D is a dihydrofuran ring or a dihydrodioxin ring.

[3] The compound or salt of the above-mentioned [1], wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms;

R¹ is

(1) a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group, or R^(1a) is bonded to onesubstituent on Ring A to form a 5-membered hydrocarbon ring, wherein theone substituent on Ring A is bonded to the position adjacent to thebonding position of R¹ on Ring A, or (2) a trimethylsilyl group;

R⁴ is a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group optionally substituted by            3- to 14-membered non-aromatic heterocyclic group(s)            optionally substituted by 1 to 3 substituents selected from            a C₁₋₆ alkyl group and an oxo-group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group,    -   (3) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 3- to        14-membered non-aromatic heterocyclic group(s) optionally        substituted by 1 to 3 substituents selected from a C₁₋₆ alkyl        group and an oxo group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group;

X is CR⁶ or N;

R⁵ is

(1) a alkyl group optionally substituted by 1 to 3 C₁₋₆ alkoxy groups,or(2) a C₁₋₆ alkoxy group;

R⁶ is a hydrogen atom; and

Ring D is not formed.

[4] The compound or salt of the above-mentioned [1], wherein R¹ is agroup represented by the formula: —C(R^(1a)) (CH₃) (CH₃) wherein R^(1a)is bonded to one substituent on Ring A to form an optionally substituted5-membered hydrocarbon ring, wherein the one substituent on Ring A isbonded to the position adjacent to the bonding position of R¹ on Ring A.[4′] The compound or salt of the above-mentioned [4], wherein the grouprepresented by the formula:

is a group represented by the formula:

wherein,

is a single bond or a double bond.[5] The compound or salt of the above-mentioned [1], wherein R⁴ iscyclopropyl or cyclobutyl, each optionally substituted.[6] The compound or salt of the above-mentioned [1], wherein

R¹ is a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1d) is bonded to one substituent on Ring A to form an optionallysubstituted 5-membered hydrocarbon ring, wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A;

R⁴ is cyclopropyl or cyclobutyl, each optionally substituted; and

Ring D is not formed.

[7]((1R,2S)-2-(((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)aceticacid or a salt thereof.[8]cis-3-(((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid or a salt thereof.[9](cis-3-(((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid or a salt thereof.[10](cis-3-(((1R)-1-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid or a salt thereof.[11] A medicament comprising the compound or salt of any of theabove-mentioned [1] to [10].[12] The medicament of the above-mentioned [11], which is a RORγtinhibitor.[13] The medicament of the above-mentioned [11], which is an agent forthe prophylaxis or treatment of psoriasis, inflammatory bowel disease(IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoidarthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis or systemic lupus erythematosus (SLE).[14] A method of inhibiting RORγt in a mammal, which comprisesadministering an effective amount of the compound or salt of any of theabove-mentioned [1] to [10] to the mammal.[15] A method for the prophylaxis or treatment of psoriasis,inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn'sdisease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma,ankylopoietic spondylarthritis or systemic lupus erythematosus (SLE) ina mammal, which comprises administering an effective amount of thecompound or salt of any of the above-mentioned [1] to [10] to themammal.[16] Use of the compound or salt of any of the above-mentioned [1] to[10] for the production of an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis or systemic lupus erythematosus(SLE). [17] The compound or salt of any of the above-mentioned [1] to[10] for use in the prophylaxis or treatment of psoriasis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis or systemic lupus erythematosus (SLE).

Effect of the Invention

The compound of the present invention has a superior RORγt inhibitoryaction, and useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, a halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, a halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- oraralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent group A.

[Substituent Group A]

(1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₅ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl) an amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group, and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably hi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) an aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) an amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) an aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl) an amino group (e.g., N-acetyl-N-methylamino) anda (C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl) an amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₅ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₅ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or alkyl-thiocarbamoyl group(e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl,diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- ordi-C₃₋₁₀ cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₅ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- oralkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₅ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), aalkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₁₋₆ alkylene group”include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH(C₃H₇)—, CH(CH(CH₃)₂)—(CH(CH₃))₂—,—CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—C(CH₃)₂— and —C(CH₃)₂—CH₂—CH₂—CH₂—.

In the present specification, examples of the “C₂₋₆ alkenylene group”include —CH—CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—,—CH═CH—C(CH₃)₂—, —CH₂—CH—CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH═CH—.

In the present specification, examples of the “C₂₋₆ alkynylene group”include —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—,—CH₂—C≡C—CH₂—, —CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—,—C≡C—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—C≡C—.

As shown in the formula:

in the present specification, when the non-aromatic Ring Q, which isfused with the aromatic Ring Q′, is present, then the non-aromatic RingQ is expressed as a ring wherein the bond C¹C² is a double bond.

For example, when the above-mentioned fused Ring QQ′ is an indane ring,then the non-aromatic Ring Q is expressed as a cyclopentene ring, andthe aromatic Ring Q′ is expressed as a benzene ring.

The definition of each symbol in the formula (I) is explained in detailin the following.

Ring A is an optionally further substituted 6-membered aromatic ring.

Examples of the “6-membered aromatic ring” of the “optionally furthersubstituted 6-membered aromatic ring” for Ring A include a benzene ring,a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ringand a triazine ring.

The “6-membered aromatic ring” of the “optionally further substituted6-membered aromatic ring” for Ring A is optionally further substituted,for example, by substituent(s) selected from the above-mentionedSubstituent Group A. The number of the substituents is, for example, 1to 3. When the number of the substituents is 2 or more, the respectivesubstituents may be the same or different.

Ring A is preferably a benzene ring optionally further substituted by 1to 3 halogen atoms (e.g., a fluorine atom).

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is an optionally substituted C₁₋₆ alkoxy-C₁₋₂ alkyl group, orR^(1a) is bonded to one substituent on Ring A to form an optionallysubstituted 5-membered hydrocarbon ring, wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A, or(2) a trimethylsilyl group.

Examples of the “C₁₋₆ alkoxy-C₁₋₂ alkyl group” of the “optionallysubstituted C₁₋₆ alkoxy-C₁₋₂ alkyl group” for R^(1a) includemethoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl,pentyloxymethyl, hexyloxymethyl, 1-methoxyethyl, 1-ethoxyethyl,1-propoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl,1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentyloxyethyl,1-hexyloxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl,2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2-sec-butoxyethyl,2-tert-butoxyethyl, 2-pentyloxyethyl and 2-hexyloxyethyl.

The “C₁₋₆ alkoxy-C₁₋₂ alkyl group” of the “optionally substitutedalkoxy-C₁₋₆ alkyl group” for R^(1a) is optionally substituted, forexample, by substituent(s) selected from the above-mentioned SubstituentGroup A. The number of the substituents is, for example, 1 to 3. Whenthe number of the substituents is 2 or more, the respective substituentsmay be the same or different.

When R^(1a) is bonded to one substituent on Ring A to form an“optionally substituted 5-membered hydrocarbon ring”, wherein the onesubstituent on Ring A is bonded to the position adjacent to the bondingposition of R¹ on Ring A, then the group represented by the formula:

is, for example, a group represented by the formula:

wherein

is a single bond or a double bond.

Examples of the “5-membered hydrocarbon ring” of the “optionallysubstituted 5-membered hydrocarbon ring” formed by R^(1a) and the onesubstituent on Ring A, wherein the one substituent on Ring A is bondedto the position adjacent to the bonding position of R¹ on Ring A,include cyclopentene and cyclopentadiene.

The “5-membered hydrocarbon ring” of the “optionally substituted5-membered hydrocarbon ring” formed by R^(1a) and the one substituent onRing A, wherein the one substituent on Ring A is bonded to the positionadjacent to the bonding position of R¹ on Ring A is optionallysubstituted, for example, by substituent(s) selected from theabove-mentioned Substituent Group A. The number of the substituents is,for example, 1 or 2. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

R¹ is preferably

(1) a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group (e.g., methoxymethyl,ethoxymethyl), or R^(1a) is bonded to one substituent on Ring A to forma 5-membered hydrocarbon ring (e.g., cyclopentene), wherein the onesubstituent on Ring A is bonded to the position adjacent to the bondingposition of R¹ on Ring A, or(2) a trimethylsilyl group.

R¹ is more preferably

(1) a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1a) is bonded to one substituent on Ring A to form a 5-memberedhydrocarbon ring (e.g., cyclopentene), wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A.

In another embodiment, R¹ is preferably a group represented by theformula: —C(R^(1a)) (CH₃) (CH₃) wherein R^(1a) is bonded to onesubstituent on Ring A to form an optionally substituted 5-memberedhydrocarbon ring (e.g., cyclopentene), wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A.

R⁴ is an optionally substituted C₃₋₆ cycloalkyl group.

The “C₃₋₆ cycloalkyl group” of the “optionally substituted C₃₋₆cycloalkyl group” for R⁴ is optionally substituted, for example, bysubstituent(s) selected from the above-mentioned Substituent Group A.The number of the substituents is, for example, 1 to 3. When the numberof the substituents is 2 or more, the respective substituents may be thesame or different.

R⁴ is preferably a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom

-   -   (1) a carboxy group, and    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) carboxy groups.

In another embodiment, R⁴ is preferably a C₃₋₆ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl) optionally substituted by 1 to 3 (preferably 1)substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl, tert-butoxycarbonyl) optionally substituted            by 3- to 14-membered non-aromatic heterocyclic group(s)            (preferably 3- to 8-membered monocyclic non-aromatic            heterocyclic group(s) (e.g., dioxolyl (preferably            1,3-dioxolyl))) optionally substituted by 1 to 3            substituents selected from a C₁₋₆ alkyl group (e.g., methyl)            and an oxo group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g.,            benzyloxycarbonyl),    -   (3) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)        optionally substituted by 3- to 14-membered non-aromatic        heterocyclic group(s) (preferably 3- to 8-membered monocyclic        non-aromatic heterocyclic group(s) (e.g., dioxolyl (preferably        1,3-dioxolyl))) optionally substituted by 1 to 3 substituents        selected from a C₁₋₆ alkyl group (e.g., methyl) and an oxo        group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl).

In this embodiment, R⁴ is more preferably a C₃₋₆ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl) optionally substituted by 1 to 3 (preferably 1)substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl) optionally substituted by 3- to 14-membered            non-aromatic heterocyclic group(s) (preferably 3- to            8-membered monocyclic non-aromatic heterocyclic group(s)            (e.g., dioxolyl (preferably 1,3-dioxolyl))) optionally            substituted by 1 to 3 substituents selected from a C₁₋₆            alkyl group (e.g., methyl) and an oxo group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g.,            benzyloxycarbonyl),    -   (3) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)        optionally substituted by 3- to 14-membered non-aromatic        heterocyclic group(s) (preferably 3- to 8-membered monocyclic        non-aromatic heterocyclic group(s) (e.g., dioxolyl (preferably        1,3-dioxolyl))) optionally substituted by 1 to 3 substituents        selected from a C₁₋₆ alkyl group (e.g., methyl) and an oxo        group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl).

In this embodiment, R⁴ is particularly preferably a C₃₋₆ cycloalkylgroup (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 to 3(preferably 1) substituents selected from

-   -   (1) a carboxy group, and    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) carboxy groups.

In another embodiment, R⁴ is preferably cyclopropyl or cyclobutyl, eachoptionally substituted.

X is CR⁶ or N.

R⁶ is a hydrogen atom or a substituent.

R⁶ is preferably a hydrogen atom.

R⁵ is an optionally substituted C₁₋₆ alkyl group or an optionallysubstituted C₁₋₆ alkoxy group.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”for R⁵ is optionally substituted, for example, by substituent(s)selected from the above-mentioned Substituent Group A. The number of thesubstituents is, for example, 1 to 5, preferably 1 to 3, When the numberof the substituents is 2 or more, the respective substituents may be thesame or different.

The “C₁₋₆ alkoxy group” of the “optionally substituted C₁₋₆ alkoxygroup” for R⁵ is optionally substituted, for example, by substituent(s)selected from the above-mentioned Substituent Group A. The number of thesubstituents is, for example, 1 to 5, preferably 1 to 3. When the numberof the substituents is 2 or more, the respective substituents may be thesame or different.

R⁵ is preferably

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy).

R⁵ is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy).

When X is CR⁶, R⁵ and R⁶ in combination optionally form Ring D, whereinRing D is an optionally substituted 5- or 6-membered oxygen-containingheterocycle containing 1 to 2 oxygen atoms as heteroatoms in addition tocarbon atoms.

Examples of the “5- or 6-membered oxygen-containing heterocyclecontaining 1 to 2 oxygen atoms as heteroatoms in addition to carbonatoms” of the “optionally substituted 5- or 6-membered oxygen-containingheterocycle containing 1 to 2 oxygen atoms as heteroatoms in addition tocarbon atoms” formed by R⁵ and R⁶ in combination include furan,dihydrofuran, dioxole (e.g., 1,2-dioxole, 1,3-dioxole), dioxin (e.g.,1,2-dioxin, 1,3-dioxin, 1,4-dioxin), dihydrodioxin (e.g.,dihydro-1,2-dioxin, dihydro-1,3-dioxin, dihydro-1,4-dioxin) and thelike.

The “5- or 6-membered oxygen-containing heterocycle containing 1 to 2oxygen atoms as heteroatoms in addition to carbon atoms” of the“optionally substituted 5- or 6-membered oxygen-containing heterocyclecontaining 1 to 2 oxygen atoms as heteroatoms in addition to carbonatoms” formed by R⁵ and R⁶ in combination is optionally substituted, forexample, by substituent(s) selected from the above-mentioned SubstituentGroup A. The number of the substituents is, for example, 1 to 3. Whenthe number of the substituents is 2 or more, the respective substituentsmay be the same or different.

When X is CR⁶, examples of Ring D formed by R⁵ and R⁶ in combinationinclude a dihydrofuran ring and a dihydrodioxin ring (e.g.,dihydro-1,4-dioxin).

The partial structure represented by the formula:

is preferably a partial structure represented by the formula:

More preferably, Ring D is not formed.

Preferable examples of the ring, group, substituent and the likeexplained in the present specification are more preferably used incombination.

Preferable examples of compound (I) include the following compounds.

[Compound A-1]

Compound (I) wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group (e.g., methoxymethyl,ethoxymethyl), or R^(1a) is bonded to one substituent on Ring A to forma 5-membered hydrocarbon ring (e.g., cyclopentene), wherein the onesubstituent on Ring A is bonded to the position adjacent to the bondingposition of R¹ on Ring A, or(2) a trimethylsilyl group;

R⁴ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionallysubstituted by 1 to 3 (preferably 1) substituents selected from

-   -   (1) a carboxy group, and    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) carboxy groups;        -   X is CR⁶ or N;        -   R⁵ is            (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted            by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or            (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy);

R⁶ is a hydrogen atom; and

when X is CR⁶, R⁵ and R⁶ in combination optionally form Ring D, whereinRing D is a dihydrofuran ring or a dihydrodioxin ring (e.g.,dihydro-1,4-dioxin).

[Compound B-1]

Compound (I) wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1a) is bonded to one substituent on Ring A to form a 5-memberedhydrocarbon ring (e.g., cyclopentene), wherein the one substituent onRing A is bonded to the position adjacent to the bonding position of R¹on Ring A;

R⁴ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionallysubstituted by 1 to 3 (preferably 1) substituents selected from

-   -   (1) a carboxy group, and    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) carboxy groups;        -   X is CR⁶ or N;        -   R⁵ is            (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted            by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or            (2) a C₁₋₆ alkoxy group (e.g., methoxy);

R⁶ is a hydrogen atom; and

Ring D is not formed.

[Compound A-2]

Compound (I) wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is

(1) a group represented by the formula: —C(R^(1a)) (CH₃) (CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group (e.g., methoxymethyl,ethoxymethyl), or R^(1a) is bonded to one substituent on Ring A to forma 5-membered hydrocarbon ring (e.g., cyclopentene), wherein the onesubstituent on Ring A is bonded to the position adjacent to the bondingposition of R¹ on Ring A, or(2) a trimethylsilyl group;

R⁴ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionallysubstituted by 1 to 3 (preferably 1) substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl, tert-butoxycarbonyl) optionally substituted            by 3- to 14-membered non-aromatic heterocyclic group(s)            (preferably 3- to 8-membered monocyclic non-aromatic            heterocyclic group(s) (e.g., dioxolyl (preferably            1,3-dioxolyl))) optionally substituted by 1 to 3            substituents selected from a C₁₋₆ alkyl group (e.g., methyl)            and an oxo group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g.,            benzyloxycarbonyl),    -   (3) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)        optionally substituted by 3- to 14-membered non-aromatic        heterocyclic group(s) (preferably 3- to 8-membered monocyclic        non-aromatic heterocyclic group(s) (e.g., dioxolyl (preferably        1,3-dioxolyl))) optionally substituted by 1 to 3 substituents        selected from a C₁₋₆ alkyl group (e.g., methyl) and an oxo        group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl);        -   X is CR⁶ or N;        -   R⁵ is            (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted            by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or            (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy);

R⁶ is a hydrogen atom; and

when X is CR⁶, R⁵ and R⁶ in combination optionally form Ring D, whereinRing D is a dihydrofuran ring or a dihydrodioxin ring (e.g.,dihydro-1,4-dioxin).

[Compound B-2]

Compound (I) wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is

(1) a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is a C₁₋₆ alkoxy-C₁₋₂ alkyl group (e.g., methoxymethyl,ethoxymethyl), or R^(1a) is bonded to one substituent on Ring A to forma 5-membered hydrocarbon ring (e.g., cyclopentene), wherein the onesubstituent on Ring A is bonded to the position adjacent to the bondingposition of R¹ on Ring A, or(2) a trimethylsilyl group;

R⁴ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionallysubstituted by 1 to 3 (preferably 1) substituents selected from

-   -   (1) a carboxy group,    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) substituents selected from        -   (i) a carboxy group,        -   (ii) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl) optionally substituted by 3- to 14-membered            non-aromatic heterocyclic group(s) (preferably 3- to            8-membered monocyclic non-aromatic heterocyclic group(s)            (e.g., dioxolyl (preferably 1,3-dioxolyl))) optionally            substituted by 1 to 3 substituents selected from a C₁₋₆            alkyl group (e.g., methyl) and an oxo group, and        -   (iii) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g.,            benzyloxycarbonyl),    -   (3) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)        optionally substituted by 3- to 14-membered non-aromatic        heterocyclic group(s) (preferably 3- to 8-membered monocyclic        non-aromatic heterocyclic group(s) (e.g., dioxolyl (preferably        1,3-dioxolyl))) optionally substituted by 1 to 3 substituents        selected from a C₁₋₆ alkyl group (e.g., methyl) and an oxo        group, and    -   (4) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl);        -   X is CR⁶ or N;        -   R⁵ is            (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted            by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or            (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy);

R⁶ is a hydrogen atom; and

Ring D is not formed.

[Compound C-2]

Compound (I) wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is a group represented by the formula: —C(R^(1a))(CH₃)(CH₃) whereinR^(1a) is bonded to one substituent on Ring

A to form a 5-membered hydrocarbon ring (e.g., cyclopentene), whereinthe one substituent on Ring A is bonded to the position adjacent to thebonding position of R¹ on Ring A;

R⁴ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionallysubstituted by 1 to 3 (preferably 1) substituents selected from

-   -   (1) a carboxy group, and    -   (2) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 (preferably 1) carboxy groups;        -   X is CR⁶ or N;        -   R⁵ is            (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted            by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or            (2) a C₁₋₆ alkoxy group (e.g., methoxy);

R⁶ is a hydrogen atom; and

Ring D is not formed.

Specific examples of compound (I) include the compounds of Examples 1 to48.

Examples of salts of compound (I) include metal salts, ammonium salts,salts with organic base, salts with inorganic acid, salts with organicacid, salts with basic or acidic amino acids, and the like. Preferableexamples of the metal salt include alkaline metal salts such as sodiumsalt, potassium salt and the like; alkaline earth metal salts such ascalcium salt, magnesium salt, barium salt and the like; aluminum salts,and the like. Preferable examples of the salt with organic base includesalts with trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike. Preferable examples of the salt with inorganic acid include saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include salts with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includesalts with arginine, lysine, ornithine and the like. Preferable examplesof the salt with acidic amino acid include salt with aspartic acid,glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferable. Forexample, if the compound has an acidic functional group therein,examples of the salt include inorganic salts such as alkaline metalsalts (e.g., sodium salt, potassium salt and the like), alkaline earthmetal salts (e.g., calcium salt, magnesium salt, barium salt and thelike) and the like; ammonium salt, and the like. If the compound has abasic functional group therein, examples of the salt thereof includesalts with inorganic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

The production method of compound (I) of the present invention isexplained below.

The intermediates produced in the following production methods may beisolated and purified according to methods such as columnchromatography, recrystallization, distillation and the like, or may bedirectly used without isolation for the next step. The intermediate maybe in the form of a salt. Examples of the salt include those exemplifiedas the salt of compound (I).

Ring A represented by the formula:

in the following production methods is used for the same meaning as RingA represented by the formula:

which is defined in compound (I) of the present invention.

Compound (I) of the present invention can be produced according to thefollowing Method A.

wherein each symbol is as defined above.

This step is a step of subjecting compound (II) or a salt thereof to anacylation reaction to convert compound (II) or a salt thereof tocompound (I).

In the acylation reaction, compound (I) can be produced by reactingcompound (II) or a salt thereof with compound (III) or a salt thereof.

Compound (III) or a salt thereof may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

The acylation reaction can be carried out according to a method knownper se, for example, the method described in Jikken Kagaku Kouza, 4thEdition, 1991, vol. 22, organic synthesis IV (the Chemical Society ofJapan ed.) and the like, or a method analogous thereto. Examples of themethod include a method using a condensing agent, a method via areactive derivative, and the like.

Examples of the condensing agent to be used for the “method using acondensing agent” include(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminiumhexafluorophosphorate (HATU),1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphorate (COMU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),N-ethyl-N′-3-dimethylaminopropylcarbodiimide and a hydrochloride thereof(WSC, WSC•HCl, EDCI), benzotriazol-1-yl-tris(dimethylamino)phosphoniumhexafluorophosphorate (BOP), diphenylphosphorylazide (DPPA), diethyl(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl) phosphate (DETBT),(3-hydroxy-3H-1,2,3-triazolo[4,5-b]pydinato)tri-1-pyrrolidinyl-phosphorushexafluorophosphorate (PyAOP),N,N,N′,N′-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uroniumtetrafluoroborate (TDBTU),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMT-MM) and a hydrate thereof and the like. They can be used alone orin combination with an additive (e.g., N-hydroxysuccinimide,1-hydroxybenzotriazole or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, etc.). The amount ofthe condensing agent to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II). Theamount of the additive to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.), esters (ethyl acetate, etc.), halogenatedhydrocarbons (chloroform, dichloromethane, etc.), amides(N,N-dimethylformamide, etc.), aromatic amines (pyridine, etc.), waterand the like, and they may be mixed as appropriate. Examples of the baseinclude alkali metal hydroxides (sodium hydroxide, potassium hydroxide,etc.), hydrogencarbonates (sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), carbonates (sodium carbonate, potassiumcarbonate, etc.), acetates (sodium acetate, etc.), tertiary amines(trimethylamine, triethylamine, N-methylmorpholine, diisopropylamine,etc.), aromatic amines (pyridine, picoline, N,N-dimethylaniline,4-dimethylaminopyridine, etc.) and the like. The amount of the base tobe used is generally about 1 to 100 mol equivalent, preferably about 1to 5 mol equivalent, per 1 mol of compound (II).

The reaction temperature is generally about −80 to 150° C., preferablyabout 0 to 50° C., and the reaction time is generally about 0.5 to 48hr, preferably 0.5 to 16 hr.

Examples of the reactive derivative in the “method via a reactivederivative” include a compound represented by the formula:

wherein LG is a leaving group, and the other symbols are as definedabove (hereinafter to be referred to as compound (IIIc)) or a saltthereof (e.g., acid halides, anhydrides, mixed anhydrides, activatedesters, etc.) and the like.

Examples of the leaving group for LG include halogen atoms (a chlorineatom, a bromine atom, a iodine atom, etc.), substituted sulfonyloxygroups (C₁₋₆ alkylsulfonyloxy groups such as methanesulfonyloxy,ethanesulfonyloxy and the like; C₆₋₁₄ arylsulfonyloxy groups such asbenzenesulfonyloxy, p-toluenesulfonyloxy and the like; C₇₋₁₅aralkylsulfonyloxy groups such as benzylsulfonyloxy group and the like,etc.), acyloxy groups (acetoxy, benzoyloxy, etc.), oxy groupssubstituted by a heterocyclic group or an aryl group(2,5-dioxo-1-pyrrolidinyl, benzotriazolyl, quinolyl, 4-nitrophenyl,etc.), heterocyclic groups (imidazolyl, etc.) and the like. In addition,LG is optionally bonded to R⁴ to form a ring, and compound (IIIc) maybe, for example, anhydrides (3-oxabicyclo[3.1.1]heptane-2,4-dione,3-oxabicyclo[3.1.0]hexane-2,4-dione,3-oxabicyclo[4.1.0]heptane-2,4-dione,3-oxabicyclo[4.2.1]nonane-2,4-dione, etc.).

The conversion of compound (III) to the reactive derivative (compound(IIIa)) can be carried out according to a method known per se. Forexample, the conversion of compound (III) to the acid halide can becarried out by employing a method using an acid halide (e.g., thionylchloride, oxalyl chloride, etc.), a method using a halide of phosphorusand phosphoric acid (e.g., phosphorus trichloride, phosphoruspentachloride, etc.), and the like. The method via a reactive derivativeis generally carried out in a solvent that does not adversely influencethe reaction, which varies depending on the kind of compound (IIIc), anda base may be added for the progress of the reaction. The kinds andamounts of the solvent and base to be used for the reaction, thereaction temperature and the reaction time are the same as in theabove-mentioned “method using a condensing agent”.

The raw material compound used in Method A can be produced according tothe following Methods B-L.

wherein R⁷ is an optionally substituted hydrocarbon group, PG is anamino-protecting group, and the other symbols are as defined above.

Examples of the amino-protecting group for PG include atert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz or Z) group, abenzyl (Bn) group, a 4-methoxybenzyl (PMB) group, a trifluoroacetyl(CF₃CO) group and the like.

(Step 1)

This step is a step of reacting compound (IV) or a salt thereof withcompound (V) or a salt thereof in the presence of a base to producecompound (VI) or a salt thereof.

Compound (IV) or a salt thereof and compound (V) or a salt thereof maybe a commercially available product, or can also be produced accordingto a method known per se or a method analogous thereto.

The amount of compound (V) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IV).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.), esters (ethyl acetate, etc.), halogenatedhydrocarbons (chloroform, dichloromethane, etc.), amides(N,N-dimethylformamide, etc.), aromatic amines (pyridine, etc.), waterand the like, and they may be mixed as appropriate. Examples of the baseinclude alkali metal hydroxides (sodium hydroxide, potassium hydroxide,etc.), hydrogencarbonates (sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), carbonates (sodium carbonate, potassiumcarbonate, etc.), acetates (sodium acetate, etc.), tertiary amines(trimethylamine, triethylamine, N-methylmorpholine, diisopropylamine,etc.), aromatic amines (pyridine, picoline, N,N-dimethylaniline,4-dimethylaminopyridine, etc.) and the like. The amount of the base tobe used is generally about 1 to 100 mol equivalent, preferably about 1to 5 mol equivalent, per 1 mol of compound (IV).

The reaction temperature is generally about −80 to 150° C., preferablyabout 0 to 50° C., and the reaction time is generally about 0.5 to 48hr, preferably 0.5 to 16 hr.

(Step 2)

This step is a step of treating compound (VI) or a salt thereof withphosphorus oxychloride and zinc(II) chloride to produce compound (VII)or a salt thereof.

The amount of the phosphorus oxychloride to be used is generally about 1to 10 mol equivalent, preferably about 1 to mol equivalent, per 1 mol ofcompound (VI).

The amount of the zinc(II) chloride to be used is generally about 0.1 to2 mol equivalent, preferably about 0.1 to 1 mol equivalent, per 1 mol ofcompound (VI).

The reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.), nitriles (acetonitrile, etc.), halogenatedhydrocarbons (chloroform, dichloromethane, etc.) and the like, and theymay be mixed as appropriate.

The reaction temperature is generally about −80 to 150° C., preferablyabout 0 to 10° C., and the reaction time is generally about 0.5 to 100hr, preferably 0.5 to 10 hr.

(Step 3)

This step is a step of subjecting compound (VII) or a salt thereof to areduction reaction to produce compound (VIII) or a salt thereof.

This reaction can be carried out in a solvent inert to the reaction byemploying various reduction reactions. The reduction reaction can becarried out according to a method known per se. Examples thereof includea method using a metal hydride, a method employing a catalytichydrogenation reaction.

Examples of the metal hydride include sodium borohydride, lithiumborohydride, zinc borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride, lithium cyanoborohydride, dibutylaluminiumhydride, aluminium hydride, lithium aluminium hydride, borane complexes(borane-THF complex, catecholborane, etc.) and the like. Among them,sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride and the like are preferable. The amount of themetal hydride to be used is, for example, about 1 to about 50 molequivalent, preferably about 1 to about 10 mol equivalent, per 1 mol ofcompound (VII).

The reduction reaction using a metal hydride is generally carried out ina solvent inert to the reaction. Examples of the solvent includearomatic hydrocarbons (toluene, xylene, etc.), aliphatic hydrocarbons(heptane, hexane, etc.), halogenated hydrocarbons (chloroform,dichloromethane, etc.), ethers (diethyl ether, tetrahydrofuran, dioxane,etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol,etc.), nitriles (acetonitrile, etc.), N,N-dimethylformamide, dimethylsulfoxide and the like. These solvents may be used in a mixture of twoor more kinds thereof in an appropriate ratio.

The reaction temperature is generally about −80° C. to about 80° C.,preferably about −40° C. to about 40° C., and the reaction time isgenerally about 5 min to about 48 hr, preferably about 1 hr to about 24hr.

The catalytic hydrogenation reaction can be carried out in the presenceof a catalyst under hydrogen atmosphere. Examples of the catalystinclude palladiums such as palladium on carbon, palladium hydroxidecarbon, palladium oxide and the like; nickels such as Raney-nickelcatalyst and the like; platinums such as platinum oxide, platinum oncarbon and the like; rhodiums such as rhodium on carbon and the like,and the like. The amount thereof to be used is generally about 0.001 toabout 1 mol equivalent, preferably about 0.01 to about 0.5 molequivalent, per 1 mol of compound (VII).

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcohols(methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene,toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, dioxane, tetrahydrofuran,etc.), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide,etc.), carboxylic acids (acetic acid, etc.), water and mixtures thereof.

The hydrogen pressure for the reaction is generally about 1 to about 50atm, preferably about 1 to about 10 atm. The reaction temperature isgenerally about 0° C. to about 150° C., preferably about 20° C. to about100° C., and the reaction time is generally about 5 min to about 72 hr,preferably about 0.5 hr to about 40 hr.

(Step 4)

This step is a step of subjecting compound (IV) or a salt thereof to acyclization reaction with compound (IX) or a salt thereof to producecompound (VIII) or a salt thereof.

Compound (IV) or a salt thereof and compound (IX) or a salt thereof usedfor this reaction may be a commercially available product, or can alsobe produced according to a method known per se or a method analogousthereto.

The amount of compound (IX) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IV).

The reaction is generally carried out in a solvent that does notadversely influence the reaction, and an acid may be added for theprogress of the reaction. Examples of the solvent that does notadversely influence the reaction include alcohols (methanol, ethanol,propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatichydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons(hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), esters (ethyl acetate, etc.) and the like.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 120° C. While the reaction time varies dependingon the kind of compound (IV) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr.

Examples of the acid to be used for the progress of the reaction includemineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid,etc.), Lewis acids (aluminium chloride, tin chloride, zinc bromide,etc.) and the like. Among them, hydrochloric acid, hydrobromic acid andaluminium chloride are preferable. While the amount of the acid to beused varies depending on the kind of solvent and the other reactioncondition, it is generally about 1 mol equivalent or more, per 1 mol ofcompound (IV).

(Step 5)

This step is a step of subjecting compound (VIII) or a salt thereof toan amino-protection reaction to produce compound (X) or a salt thereof.

When the amino group is protected by a Boc group, the reaction iscarried out by reacting compound (VIII) or a salt thereof withdi-tert-butyl dicarbonate (Boc₂O) in the presence of a base, in asolvent that does not adversely influence the reaction.

Examples of the base to be used in this step include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. Among them, sodium hydride and triethylamine arepreferable. While the amount of the base to be used varies depending onthe kind of solvent and the other reaction condition, it is generallyabout 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (VIII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane,etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.),amides (dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.),and water and the like. These solvents may be used in a mixture of twoor more kinds thereof in an appropriate ratio.

The amount of the Boc₂O used in this step is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VIII).

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (VIII)or a salt thereof, the reaction temperature and the like, it is, forexample, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

When the amino group is protected by a Cbz (Z) group, the reaction iscarried out by reacting compound (VIII) or a salt thereof with benzylchloroformate in a solvent that does not adversely influence thereaction. The kinds and amounts of the base, solvent and reagent to beused in this step, the reaction temperature and the reaction time arethe same as in the above-mentioned protection of the amino group by aBoc group.

When the amino group is protected by a Bn group, the reaction is carriedout by reacting compound (VIII) or a salt thereof with benzaldehyde in asolvent that does not adversely influence the reaction, and thentreating the resulting compound with a reducing agent, or by reactingcompound (VIII) or a salt thereof with benzyl bromide in the presence ofa base, in a solvent that does not adversely influence the reaction.

When compound (VIII) or a salt thereof is reacted with benzaldehyde,examples of the solvent that does not adversely influence the reactioninclude hydrocarbons (heptane, hexane, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, dichloromethane,1,2-dichloroethane, etc.), ethers (diethyl ether, tetrahydrofuran,dioxane, etc.), esters (ethyl acetate, t-butyl acetate, etc.), alcohols(methanol, ethanol, 2-propanol, etc.), nitriles (acetonitrile,butyronitrile, etc.), amides (dimethylformamide, dimethylacetamide,etc.), sulfoxides (dimethyl sulfoxide, etc.), and mixed solventsthereof.

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., sodium borohydride, lithium borohydride, zincborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,lithium cyanoborohydride, diisobutylaluminium hydride, aluminiumhydride, lithium aluminium hydride), borane complexes (borane-THFcomplex, catecholborane, etc.) and the like. The amount of the metalhydride to be used is about 1 to about 50 mol equivalent, per 1 mol ofcompound (VIII).

In this reaction, a catalyst may be added for the progress of thereaction, if necessary. Examples of the catalyst include mineral acids(hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylicacids (formic acid, acetic acid, propionic acid, trifluoroacetic acid,etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid,etc.), Lewis acids (aluminium chloride, zinc chloride, zinc bromide,boron trifluoride, titanium chloride, etc.), acetates (sodium acetate,potassium acetate, etc.), molecular sieves (molecular sieves 3A, 4A, 5A,etc.), dehydrating agents (magnesium sulfate, etc.) and the like. Theamount of the catalyst to be used is generally about 0.01 to 50 molequivalent, preferably about 0.1 to 10 mol equivalent, per 1 mol ofcompound (VIII).

The amount of the benzaldehyde to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VIII).

The reaction temperature is generally about 0° C. to 200° C., preferablyabout 20° C. to 150° C., and the reaction time is generally about 0.5 hrto 48 hr, preferably about 0.5 hr to 24 hr.

When compound (VIII) or a salt thereof is reacted with benzyl bromide,examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. Among them, potassium carbonate is preferable. Whilethe amount of the base to be used varies depending on the kind ofsolvent and the other reaction condition, it is generally about 1 to 10mol equivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (VIII).

The amount of the benzyl bromide to be used is generally about 1 to 10mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VIII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane,etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.),amides (dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.)and the like. Among them, acetonitrile is preferable. These solvents maybe used in a mixture of two or more kinds thereof in an appropriateratio.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the kind of compound (VIII) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 100 hr,preferably about 0.5 to 24 hr.

When the amino group is protected by a PMB group, the reaction iscarried out by reacting (VIII) or a salt thereof with4-methoxybenzaldehyde in a solvent that does not adversely influence thereaction, and then treating the resulting compound with a reducingagent.

The kinds and amounts of the solvent, reducing agent, reagent andadditive to be used in this step, the reaction temperature and thereaction time are the same as in the above-mentioned protection of theamino group by a Bn group.

When the amino group is protected by a CF₃CO group, the reaction iscarried out by reacting compound (VIII) or a salt thereof withtrifluoroacetic anhydride in the presence of a base, in a solvent thatdoes not adversely influence the reaction. The kinds and amounts of thebase, solvent and reagent to be used in this step, the reactiontemperature and the reaction time are the same as in the above-mentionedprotection of the amino group by a Boc group.

(Step 6)

This step is a step of subjecting compound (X) or a salt thereof tohydrolysis to convert compound (X) or a salt thereof to compound (XI) ora salt thereof. This reaction can be carried out according to a methodknown per se, generally in the presence of an acid or a base, in asolvent that does not adversely influence the reaction, if necessary.

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), carboxylic acids (acetic acid,trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like, andthey may be used in a mixture of two or more kinds thereof. While theamount of the acid to be used varies depending on the kind of solventand the other reaction condition, it is generally about 0.1 molequivalent or more, per 1 mol of compound (X). They may be used as asolvent.

Examples of the base include inorganic bases (alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike, alkali metal hydrogencarbonates such as sodium hydrogencarbonate,potassium hydrogencarbonate and the like, alkali metal carbonates suchas sodium carbonate, potassium carbonate and the like, alkoxides such assodium methoxide, sodium ethoxide and the like, etc.), organic bases(amines such as trimethylamine, triethylamine, diisopropylethylamine andthe like, cyclic amines such as pyridine, 4-dimethylaminopyridine andthe likes, etc.) and the like. Among them, sodium hydroxide ispreferable. While the amount of the base to be used varies depending onthe kind of solvent and the other reaction condition, it is generallyabout 0.1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (X).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, t-butanol, etc.), hydrocarbons (benzene, toluene, xylene,hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), carboxylic acids (acetic acid, etc.), amides(dimethylformamide, dimethylacetamide, etc.), sulfoxides (dimethylsulfoxide, etc.), water and the like. Among them, ethanol,tetrahydrofuran and water are preferable. These solvents may be used ina mixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (X) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr.

(Step 7)

This step is a step of reacting compound (XI) or a salt thereof withcompound (XII) or a salt thereof in the presence of a condensing agentto produce compound (XIII) or a salt thereof.

This step can be carried out in the same manner as in the “method usinga condensing agent” in Method A.

(Step 8)

This step is a step of subjecting compound (XIII) or a salt thereof to adeprotection reaction to produce compound (II) or a salt thereof.

The deprotection reaction can be carried out according to a method knownper se (e.g., the method described in “Protective Groups in OrganicSynthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999) (Theodora W. Greene,Peter G. M. Wuts)).

When PG is a Boc group, the deprotection reaction can be carried out inthe presence of an acid, in a solvent that does not adversely influencethe reaction.

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), carboxylic acids (acetic acid,trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like, andthey may be used in a mixture of two or more kinds thereof. While theamount of the acid to be used varies depending on the kind of solventand the other reaction condition, it is generally about 0.1 molequivalent or more, per 1 mol of compound (XIII). They may be used as asolvent.

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene,xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), esters (ethyl acetate, etc.), carboxylic acids(acetic acid, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), water, and mixed solvents thereof.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (XIII) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 100 hr,preferably about 0.5 to 24 hr.

When PG is a Bn group, a Cbz (Z) group or a PMB group, the deprotectionreaction can be carried out by a catalytic hydrogenation reaction, anoxidation reaction or an acid hydrolysis.

The catalytic hydrogenation reaction can be carried out in the presenceof a catalyst under hydrogen atmosphere. Examples of the catalystinclude palladiums such as palladium on carbon, palladium hydroxidecarbon, palladium oxide and the like; nickels such as Raney-nickelcatalyst and the like; platinums such as platinum oxide, platinum oncarbon and the like; rhodiums such as rhodium on carbon and the like,and the like. The amount thereof to be used is generally about 0.001 to1 mol equivalent, preferably about 0.01 to 0.5 mol equivalent, per 1 molof compound (XIII).

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcoholssuch as methanol, ethanol, propanol, butanol and the like; hydrocarbonssuch as benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such as diethylether, dioxane, tetrahydrofuran and the like; esters such as ethylacetate and the like; amides such as N,N-dimethylformamide and the like;carboxylic acids such as acetic acid and the like; water and mixturesthereof.

The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm. The reaction temperature is generallyabout 0° C. to 150° C., preferably about 20° C. to 100° C., and thereaction time is generally about 5 min to 72 hr, preferably about 0.5 hrto 40 hr.

Examples of the oxidizing agent to be used for the oxidation reactioninclude ammonium cerium(IV) nitrate. The amount thereof to be used isabout 1 to about 50 mol equivalent, per 1 mol of compound (XIII).

The oxidation reaction is carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includenitriles (e.g., acetonitrile), hydrocarbons (e.g., benzene, toluene,xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform),ethers (e.g., diethyl ether, dioxane, tetrahydrofuran), amides (e.g.,N,N-dimethylformamide), water and mixtures thereof.

The reaction temperature is generally about 0° C. to 150° C., preferablyabout 20° C. to 100° C., and the reaction time is generally about 5 minto 72 hr, preferably about 0.5 hr to 40 hr.

Examples of the acid to be used for the acid hydrolysis includetrifluoroacetic acid. The acid may be used as a solvent. The reactiontemperature is generally about 0° C. to 150° C., preferably about 0° C.to 30° C., and the reaction time is generally about 5 min to 72 hr,preferably about 0.5 hr to 40 hr.

When PG is a CF₃CO group, the deprotection reaction can be carried outin the presence of a base, in a solvent that does not adverselyinfluence the reaction.

Examples of the base include inorganic bases (alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike, alkali metal hydrogencarbonates such as sodium hydrogencarbonate,potassium hydrogencarbonate and the like, alkali metal carbonates suchas sodium carbonate, potassium carbonate and the like, alkoxides such assodium methoxide, sodium ethoxide and the like, etc.) and the like. Theamount of the base to be used is about 1 to 100 mol equivalent,preferably about 1 to 20 mol equivalent, per 1 mol of compound (XIII).

Examples of the solvent that does not adversely influence the reactioninclude hydrocarbons (benzene, toluene, xylene, hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), amides (N,N-dimethylformamide,N,N-dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide, etc.),water and the like. These solvents may be used in a mixture of two ormore kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (XIII) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 24 hr,preferably about 0.5 to 2 hr.

[Method C]

When compound (XI) is a compound represented by the formula:

wherein R⁸ is an optionally substituted C₁₋₆ alkyl group, and the othersymbols are as defined above (hereinafter to be referred to as compound(XIa)) or a salt thereof, this compound can be produced according toMethod C.

wherein Boc is a tert-butoxycarbonyl group, and the other symbols are asdefined above.

(Step 1)

This step is a step of subjecting compound (IVa) to a cyclizationreaction with compound (IXa) to produce compound (VIIIa).

Compound (IVa) and compound (IXa) used for this reaction may be acommercially available product, or can also be produced according to amethod known per se or a method analogous thereto.

The amount of compound (IXa) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IVa).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include alcohols (methanol, ethanol, propanol, 2-propanol,butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene,toluene, xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), esters (ethyl acetate, etc.) and the like.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the reaction temperature and the like, it is, for example, about 0.5to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (VIIIa) to a protectionreaction by a Boc group to produce compound (Xa).

This reaction is carried out by reacting compound (VIIIa) withdi-tert-butyl dicarbonate (Boc₂O) in the presence of a base, in asolvent that does not adversely influence the reaction.

Examples of the base to be used in this step include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. Among them, sodium hydride and triethylamine arepreferable. While the amount of the base to be used varies depending onthe kind of solvent and the other reaction condition, it is generallyabout 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (VIIIa).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane,etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.),amides (dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.),and water and the like. These solvents may be used in a mixture of twoor more kinds thereof in an appropriate ratio.

The amount of the Boc₂O used in this step is about 1 to mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (VIIIa).

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (VIIIa)or a salt thereof, the reaction temperature and the like, it is, forexample, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 3)

This step is a step of subjecting compound (Xa) to an alkylationreaction with a compound represented by the formula:

R⁸-LG  (XIV)

wherein each symbol is as defined above (hereinafter to be referred toas compound (XIV)) or a salt thereof, in the presence of a base, toproduce compound (XV) or a salt thereof.

Compound (XIV) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the base used for this reaction include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like) and the like. While the amount of the base to be used variesdepending on the kind of solvent and the other reaction condition, it isgenerally about 1 to 10 mol equivalent, preferably about 1 to 5 malequivalent, per 1 mol of compound (Xa).

The amount of compound (XIV) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (Xa).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (dimethylformamide, etc.), sulfoxides (dimethylsulfoxide, etc.) and the like. These solvents may be used in a mixtureof two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −75 to 200° C.,preferably about −10 to 30° C. While the reaction time varies dependingon the kind of compound (Xa), the reaction temperature and the like, itis, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 4)

This step is a step of subjecting compound (XV) or a salt thereof tohydrolysis to convert compound (XV) or a salt thereof to compound (XIa)or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method B

[Method D]

When compound (XI) is a compound represented by the formula:

wherein R⁸ is an optionally halogenated C₁₋₆ alkyl group, and the othersymbols are as defined above (hereinafter to be referred to as compound(XIb)) or a salt thereof, this compound can be produced according toMethod D.

wherein each symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (Xa) to a triflation reactionto produce compound (XVI).

This reaction can be carried out in the presence of a base and atriflating agent.

Examples of the base used for this reaction include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, etc.), organic bases (amines such as trimethylamine,triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-eneand the like, cyclic amines such as pyridine, 4-dimethylaminopyridineand the like, etc.) and the like. While the amount of the base to beused varies depending on the kind of solvent and the other reactioncondition, it is generally about 1 to 10 mol equivalent, preferablyabout 1 to 5 mol equivalent, per 1 mol of compound (Xa).

Examples of the triflating agent used for this reaction includetrifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride,N-phenylbis(trifluoromethanesulfonimide),N-(5-chloro-2-pyridyl)triflimide and the like. While the amount of thetriflating agent to be used varies depending on the kind of solvent andthe other reaction condition, it is generally about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (Xa).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (dimethylformamide, etc.), sulfoxides (dimethylsulfoxide, etc.) and the like. These solvents may be used in a mixtureof two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (Xa),the reaction temperature and the like, it is, for example, about 0.5 to100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (XVI) to a cyanation reactionto produce compound (XVII).

This reaction can be carried out using a cyanating agent in the presenceof a transition metal catalyst, in a solvent that does not adverselyinfluence the reaction.

Examples of the transition metal catalyst used for this reaction includepalladium catalysts (palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium, etc.), nickel catalysts (nickelchloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-tert-butylphosphine, S-Phos, BINAP, etc.) canbe used. While the amount of the transition metal catalyst to be usedvaries depending on the kind of solvent and the other reactioncondition, it is generally about 0.001 to 1 mol equivalent, preferablyabout 0.1 to 0.5 mol equivalent, per 1 mol of compound (XVI). The amountof the ligand to be used is about 0.001 to 1 mol equivalent, per 1 molof compound (XVI).

Examples of the cyanating agent used for this reaction include zinccyanide, copper cyanide and the like. While the amount of the cyanatingagent to be used varies depending on the kind of solvent and the otherreaction condition, it is generally about 0.5 to 10 mol equivalent,preferably about 0.5 to 2 mol equivalent, per 1 mol of compound (XVI).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane,etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.),amides (dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.)and the like. These solvents may be used in a mixture of two or morekinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −10 to 200° C.While the reaction time varies depending on the kind of compound (XVI),the reaction temperature and the like, it is, for example, about 0.5 to100 hr, preferably about 0.5 to 24 hr. Where necessary, the reaction maybe carried out under microwave irradiation.

(Step 3)

This step is a step of subjecting compound (XVII) to a reductionreaction to produce compound (XVIII).

The reduction reaction can be carried out in the presence ofRaney-nickel catalyst, under hydrogen atmosphere or using a hydrogendonor.

The amount of the Raney-nickel catalyst to be used is generally about0.001 to 10 mol equivalent, preferably about 0.01 to 2 mol equivalent,per 1 mol of compound (XVII).

The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm.

Examples of the hydrogen donor include sodium hypophosphite. The amountthereof to be used is generally about 1 to 100 mol equivalent,preferably about 1 to 20 mol equivalent, per 1 mol of compound (XVII).

This reaction is carried out in a solvent inert to the reaction.Examples of the solvent include alcohols such as methanol, ethanol,propanol, butanol and the like; hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,chloroform and the like; ethers such as diethyl ether, dioxane,tetrahydrofuran and the like; esters such as ethyl acetate and the like;amides such as N,N-dimethylformamide and the like; carboxylic acids suchas acetic acid and the like; bases such as pyridine, triethylamine andthe like; water and mixtures thereof.

The reaction temperature is generally about 0° C. to 150° C., preferablyabout 20° C. to 100° C., and the reaction time is generally about 5 minto 72 hr, preferably about 0.5 hr to 40 hr.

(Step 4)

This step is a step of treating compound (XVIII) with a reducing agentto produce compound (XIX).

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., sodium borohydride, lithium borohydride, zincborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,lithium cyanoborohydride) and the like. The amount of the metal hydrideto be used is about 1 to 50 mol equivalent, per 1 mol of compound(XVIII).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include alcohols such asmethanol, ethanol, propanol, butanol and the like; hydrocarbons such asbenzene, toluene, xylene and the like; halogenated hydrocarbons such asdichloromethane, chloroform and the like; ethers such as diethyl ether,dioxane, tetrahydrofuran and the like; esters such as ethyl acetate andthe like; amides such as N,N-dimethylformamide and the like; carboxylicacids such as acetic acid and the like; water and mixtures thereof.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 50° C. While the reaction time varies depending onthe kind of compound (XVIII), the reaction temperature and the like, itis, for example, about 0.1 to 100 hr, preferably about 0.1 to 6 hr.

(Step 5)

This step is a step of subjecting compound (XIX) to a mesylationreaction to convert compound (XIX) into a compound represented by theformula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (XIXa)), and then reacting compound (XIXa) with a compoundrepresented by the formula:

R^(B)—CH  (XIVa)

wherein each symbol is as defined above (hereinafter to be referred toas compound (XIVa)) or a salt thereof in the presence of a base toproduce compound (XVa) or a salt thereof.

The mesylation reaction can be carried out in the presence of a base anda mesylating agent.

Compound (XIVa) or a salt thereof may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

The kind and amount of the base for the mesylation reaction are the sameas in Step 1 of Method D.

Examples of the mesylating agent include methanesulfonyl chloride andthe like. While the amount of the mesylating agent to be used variesdepending on the kind of solvent and the other reaction condition, it isgenerally about 1 to 10 mol equivalent, preferably about 1 to 5 molequivalent, per 1 mol of compound (XIX).

Examples of the base for the reaction of compound (XIXa) with compound(XIVa) or a salt thereof in the presence of a base include organicamines (trimethylamine, triethylamine, diisopropylamine,N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine,N,N-dimethylaniline, etc.), alkali metal salts (sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, cesium carbonate, sodium phosphate, potassiumphosphate, sodium hydroxide, potassium hydroxide, lithium acetate,etc.), metal hydrides (potassium hydride, sodium hydride, etc.) and thelike. The amount of the base to be used is about 1 to 10 mol equivalent,per 1 mol of compound (XIXa).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include hydrocarbons (benzene, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.),nitriles (acetonitrile, etc.), ethers (dimethoxyethane,tetrahydrofuran), aprotic polar solvents (dimethylformamide, dimethylsulfoxide, hexamethylphosphoroamide, etc.) and mixtures thereof.Compound (XIVa) may be used as a solvent.

The reaction temperature is generally about −100 to 200° C., preferablyabout −20 to 100° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr.

(Step 6)

This step is a step of subjecting compound (XVa) or a salt thereof tohydrolysis to convert compound (XVa) or a salt thereof to compound (XIb)or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method R.

[Method E]

When compound (XI) is a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (XIc)) or a salt thereof, this compound can be producedaccording to Method E.

wherein each symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (XX) or a salt thereof to ahydroxymethylation reaction to convert compound (XX) or a salt thereofto compound (XXI) or a salt thereof.

Compound (XX) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto.

In this reaction, compound (XXI) or a salt thereof can be produced byreacting compound (XX) or a salt thereof with paraformaldehyde in thepresence of a base.

Examples of the base used for this reaction include organic lithiumreagents (e.g., n-butyllithium, phenyllithium, lithiumdiisopropylamide),alkali metal hydrides (e.g., sodium hydride, lithium hydride) and thelike. While the amount of the base to be used varies depending on thekind of solvent and the other reaction condition, it is generally about1 to 10 mol equivalent, preferably about 1 to 2 mol equivalent, per 1mol of compound (XX).

The amount of the paraformaldehyde used for this reaction to be used isabout 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (XX).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.) and the like. These solvents may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −100 to 50° C.,preferably about −78 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (XXI) or a salt thereof tophthalimidation reaction to convert compound (XXI) or a salt thereof tocompound (XXII) or a salt thereof.

In this reaction, compound (XXII) or a salt thereof can be produced byreacting compound (XXI) or a salt thereof with phthalimide in thepresence of an azodicarboxylate reagent and triphenylphosphine.

Examples of the azodicarboxylate reagent used for this reaction includediethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD).While the amount of the azodicarboxylate reagent to be used variesdepending on the kind of solvent and the other reaction condition, it isgenerally about 1 to 5 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (XXI).

The amount of the triphenylphosphine used for this reaction to be usedis about 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent,per 1 mol of compound (XXI).

The amount of the phthalimide used for this reaction to be used is about1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 molof compound (XXI).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.) and the like. These solvents may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 50° C.,preferably about 0 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 3)

This step is a step of reacting compound (XXII) or a salt thereof withhydrazine to convert compound (XXII) or a salt thereof to compound (IVb)or a salt thereof.

The amount of the hydrazine used for this reaction to be used is about 1to 20 mol equivalent, preferably about 3 to 7 mol equivalent, per 1 molof compound (XXII).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include alcohols (methanol, ethanol, propanol, 2-propanol,butanol, isobutanol, t-butanol, etc.), water, nitriles (acetonitrile,etc.), amides (dimethylformamide, dimethylacetamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), ethers (diethyl ether, diisopropyl ether,t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.)and the like. These solvents may be used in a mixture of two or morekinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 0 to 100° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 4)

This step is a step of subjecting compound (XXIII) or a salt thereof toa cyanomethylation reaction to convert compound (XXIII) or a saltthereof to compound (XXIV) or a salt thereof.

Compound (XXIII) or a salt thereof may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

In this step, compound (XXIV) or a salt thereof is produced by treatingacetonitrile in the presence of n-butyllithium to producelithioacetonitrile, and then reacting the lithioacetonitrile withcompound (XXIII) or a salt thereof.

The amounts of the n-butyllithium and acetonitrile used in theproduction of the lithioacetonitrile to be used are about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (XXIII), respectively.

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.) and the like. These solvents may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −100 to 50° C.,preferably about −78 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 8 hr.

(Step 5)

This step is a step of subjecting compound (XXIV) or a salt thereof to acatalytic hydrogenation reaction using a transition metal catalyst toproduce compound (IVb) or a salt thereof.

Examples of the transition metal catalyst used for this reaction includepalladiums (palladium on carbon, palladium hydroxide, palladium oxide,etc.), nickels (Raney-nickel, etc.), platinums (platinum oxide, platinumon carbon, etc.), rhodiums (rhodium acetate, rhodium on carbon, etc.)and the like. The amount thereof to be used is, for example, about 0.001to 1 equivalent, preferably about 0.01 to 0.5 equivalent, per 1 mol ofcompound (XXIV).

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcohols(methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene,toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, dioxane, tetrahydrofuran,etc.), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide,etc.), carboxylic acids (acetic acid, etc.), water and mixtures thereof.The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm.

The reaction temperature is generally about 0 to 150° C., preferablyabout 20 to 100° C., and the reaction time is generally about 5 min to72 hr, preferably about 0.5 to 40 hr.

(Step 6)

This step is a step of subjecting compound (IVb) or a salt thereof to acyclization reaction with compound (IXa) to produce compound (XXV) or asalt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 1 of Method C.

(Step 7)

This step is a step of subjecting compound (XXV) or a salt thereof to anamino-protection reaction with a t-butoxycarbonyl (Boc) group to producecompound (XXVI) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 5 of Method B.

(Step 8)

This step is a step of subjecting compound (XXVI) or a salt thereof toan O-methylation reaction to produce compound (XXVII) or a salt thereof.

In this reaction, compound (XXVII) or a salt thereof can be produced byreacting compound (XXVI) or a salt thereof with methyl iodide in thepresence of a base.

Examples of the base used for this reaction include silver salts (e.g.,silver carbonate, silver nitrate, silver sulfate, silver acetate, silverchloride).

The amount of the silver salt used for this reaction to be used is about1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 molof compound (XXVI).

This step can be carried out in the same manner as in the methoddescribed in Step 3 of Method C.

(Step 9) This step is a step of subjecting compound (XXVII) or a saltthereof to hydrolysis to convert compound (XXVII) or a salt thereof tocompound (XIc) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method B.

[Method F]

When compound (XII) is a compound represented by the formula:

(hereinafter to be referred to as compound (XIIa)) or a salt thereof,this compound can be produced according to Method F.

(Step 1)

This step is a step of reacting compound (XXVIII) with a silylatingagent in the presence of a transition metal catalyst or in thenon-presence of a transition metal catalyst to produce compound (XXIX).

Compound (XXVIII) may be a commercially available product.

Examples of the transition metal catalyst used for this reaction includepalladium catalysts (palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium, etc.), nickel catalysts (nickelchloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-t-butylphosphine, S-Phos, BINAP, etc.) or abase (e.g., organic amines (trimethylamine, triethylamine,diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium phosphate, potassium phosphate, sodium hydroxide,potassium hydroxide, etc.), metal hydrides (potassium hydride, sodiumhydride, etc.), alkali metal alkoxides (sodium methoxide, sodiumethoxide, sodium t-butoxide, potassium t-butoxide, etc.), alkalidisilazides (lithium disilazide, sodium disilazide, potassiumdisilazide, etc.)) may be added. A metal oxide (copper oxide, silveroxide, etc.) and the like may be used as a co-catalyst. The amount ofthe catalyst to be used is about 0.0001 to 1 mol equivalent, preferablyabout 0.01 to 0.5 mol equivalent, per 1 mol of compound (XXVIII). Theamount of the ligand to be used is about 0.0001 to 4 mol equivalent,preferably about 0.01 to 2 mol equivalent, per 1 mol of compound(XXVIII). The amount of the base to be used is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXVIII). The amount of the co-catalyst to be used is about0.0001 to 4 mol equivalent, preferably about 0.01 to 2 mol equivalent,per 1 mol of compound (XXVIII).

Examples of the silylating agent include 1,1,1,2,2,2-hexamethyldisilaneand chlorotrimethylsilane. The amount of the silylating agent to be usedis about 1 to 10 mol equivalent, preferably about 1 to 4 mol equivalent,per 1 mol of compound (XXVIII).

The solvent is not limited as long as it does not adversely influencethe reaction, and examples thereof include hydrocarbons (benzene,toluene, xylene, etc.), halogenated hydrocarbons (chloroform,1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers(dimethoxyethane, tetrahydrofuran), alcohols (methanol, ethanol, etc.),aprotic polar solvents (dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide, etc.), water and mixtures thereof.

The reaction temperature is generally about −100 to 200° C., preferablyabout −80 to 150° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr. Where necessary, the reaction may becarried out under microwave irradiation.

(Step 2)

This step is a step of subjecting compound (XXIX) to a catalytichydrogenation reaction using a transition metal catalyst to producecompound (XIIa) or a salt thereof.

Examples of the transition metal catalyst used for this reaction includepalladiums (palladium on carbon, palladium hydroxide, palladium oxide,etc.), nickels (Raney-nickel, etc.), platinums (platinum oxide, platinumon carbon, etc.), rhodiums (rhodium acetate, rhodium on carbon, etc.)and the like. The amount thereof to be used is, for example, about 0.001to 1 equivalent, preferably about 0.01 to 0.5 equivalent, per 1 mol ofcompound (XXIX). The catalytic hydrogenation reaction is generallycarried out in a solvent inert to the reaction. Examples of the solventinclude alcohols (methanol, ethanol, propanol, butanol, etc.),hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.), esters (ethyl acetate, etc.), amides(N,N-dimethylformamide, etc.), carboxylic acids (acetic acid, etc.),water and mixtures thereof. The hydrogen pressure for the reaction isgenerally about 1 to 50 atm, preferably about 1 to 10 atm.

The reaction temperature is generally about 0 to 150° C., preferablyabout 20 to 100° C., and the reaction time is generally about 5 min to72 hr, preferably about 0.5 to 40 hr.

[Method G]

When compound (XII) is a compound represented by the formula:

(hereinafter to be referred to as compound (XIIb)) or a salt thereof,this compound can be produced according to Method G1 or Method G2.

(Step 1)

This step is a step of subjecting compound (XXX) to a carbon-carbonbond-forming reaction with ethyl acrylate in the presence of atransition metal catalyst to produce compound (XXXI).

Compound (XXX) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the transition metal catalyst used for this reaction includepalladium catalysts (palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium, etc.), nickel catalysts (nickelchloride, etc.) and the like. Where necessary, a ligand(tris(2-methylphenyl)phosphane, triphenylphosphine,tri-t-butylphosphine, S-Phos, BINAP, etc.) or a base (e.g., organicamines (trimethylamine, triethylamine, diisopropylamine,N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine,N,N-dimethylaniline, etc.), alkali metal salts (sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, cesium carbonate, sodium phosphate, potassiumphosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides(potassium hydride, sodium hydride, etc.), alkali metal alkoxides(sodium methoxide, sodium ethoxide, sodium t-butoxide, potassiumt-butoxide, etc.), alkali disilazides (lithium disilazide, sodiumdisilazide, potassium disilazide, etc.)) may be added. A metal oxide(copper oxide, silver oxide, etc.) and the like may be used as aco-catalyst. The amount of the catalyst to be used is about 0.0001 to 1mol equivalent, preferably about 0.01 to 0.5 mol equivalent, per 1 molof compound (XXX). The amount of the ligand to be used is about 0.0001to 4 mol equivalent, preferably about 0.01 to 2 mol equivalent, per 1mol of compound (XXX). The amount of the base to be used is about 1 to10 mol equivalent, per 1 mol of compound (XXX). Base may be used as asolvent. The amount of the co-catalyst to be used is about 0.0001 to 4mol equivalent, preferably about 0.01 to 2 mol equivalent, per 1 mol ofcompound (XXX).

The solvent is not limited as long as it does not adversely influencethe reaction, and examples thereof include hydrocarbons (benzene,toluene, xylene, etc.), halogenated hydrocarbons (chloroform,1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers(dimethoxyethane, tetrahydrofuran), alcohols (methanol, ethanol, etc.),aprotic polar solvents (dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide, etc.), amines (triethylamine, etc.), water andmixtures thereof.

The reaction temperature is generally about −100 to 200° C., preferablyabout −80 to 150° C., and the reaction time is generally about 0.5 to 72hr, preferably about 0.5 to 48 hr. Where necessary, the reaction may becarried out under microwave irradiation.

(Step 2)

This step is a step of subjecting compound (XXXI) to a reductionreaction to produce compound (XXXII) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in the “method employing a catalytic hydrogenation reaction”in Step 3 of Method B.

(Step 3)

This step is a step of reacting compound (XXXII) with methylmagnesiumbromide to produce compound (XXXIII).

The amount of the methylmagnesium bromide used for this reaction to beused is about 2 to 10 mol equivalent, preferably about 2 to 5 molequivalent, per 1 mol of compound (XXXII).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include ethers (diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.) and thelike. These solvents may be used in a mixture of two or more kindsthereof in an appropriate ratio.

The reaction temperature is, for example, within about 0 to 100° C.,preferably about 0 to 30° C., and the reaction time is, for example,about 0.5 to 24 hr, preferably about 0.5 to 2 hr.

(Step 4)

This step is a step of subjecting compound (XXXIII) to a cyclizationreaction using an acid to produce compound (XXXIV).

Examples of the acid used for this reaction include mineral acids(hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), organicacids (polyphosphoric acid, methanesulfonic acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like.Among them, polyphosphoric acid is preferable. While the amount of theacid to be used varies depending on the kind of solvent and the otherreaction condition, it is generally about 1 mol equivalent or more, per1 mol of compound (XXXIII).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.) and the like. An acid may be used as a solvent.

The reaction temperature is, for example, within about 0 to 150° C.,preferably about 10 to 190° C., and the reaction time is, for example,about 0.5 to 24 hr, preferably about 0.5 to 2 hr.

(Step 5)

This step is a step of subjecting compound (XXXIV) to a de-methylationreaction to produce compound (XXXV).

The de-methylation reaction can be carried out according a method knownper se (e.g., the method described in “Protective Groups in OrganicSynthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999) (Theodora W. Greene,Peter G. M. Wuts)). For example, compound (XXXV) can be obtained bytreating compound (XXXIV) with aluminium chloride in the presence of1-dodecanethiol.

The amount of the 1-dodecanethiol to be used is about 1 to 10 molequivalent, per 1 mol of compound (XXXIV). The amount of the aluminiumchloride to be used is about 1 to 10 mol equivalent, per 1 mol ofcompound (XXXIV).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include hydrocarbonssuch as benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such as diethylether, dioxane, tetrahydrofuran and the like; and the like.

The reaction temperature is, for example, within about −50 to 100° C.,preferably about −10 to 50° C. While the reaction time varies dependingon the reaction temperature and the like, it is, for example, about 0.1to 100 hr, preferably about 0.1 to 6 hr.

(Step 6)

This step is a step of subjecting compound (XXXV) to a triflationreaction to produce compound (XXXVI).

This step can be carried out in the same manner as in the methoddescribed in Step 1 of Method D.

(Step 7)

This step is a step of reacting compound (XXXVI) with an aminating agentin the presence of a transition metal catalyst, and then treating theresulting compound with an acid or hydroxyamine hydrochloride and sodiumacetate to produce compound (XIIb) or a salt thereof.

Examples of the transition metal catalyst used for this reaction includepalladium catalysts (palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium(0), etc.), nickel catalysts(nickel chloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-t-butylphosphine, S-Phos, BINAP,2′-(di-tert-butylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine,XANTPHOS, etc.) or a base (e.g., organic amines (trimethylamine,triethylamine, diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium phosphate, potassium phosphate, sodium hydroxide,potassium hydroxide, lithium acetate, etc.), metal hydrides (potassiumhydride, sodium hydride, etc.), alkali metal alkoxides (sodiummethoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide,etc.), alkali disilazides (lithium disilazide, sodium disilazide,potassium disilazide, etc.)) may be added. A metal oxide (copper oxide,silver oxide, etc.) and the like may be used as a co-catalyst. Theamount of the catalyst to be used is about 0.0001 to 1 mol equivalent,preferably about 0.01 to 0.5 mol equivalent, per 1 mol of compound(XXXVI). The amount of the ligand to be used is about 0.0001 to 4 molequivalent, preferably about 0.01 to 2 mol equivalent, per 1 mol ofcompound (XXXVI). The amount of the base to be used is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXXVI). The amount of the co-catalyst to be used is about0.0001 to 4 mol equivalent, preferably about 0.01 to 2 mol equivalent,per 1 mol of compound (XXXVI).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include hydrocarbons (benzene, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.),nitriles (acetonitrile, etc.), ethers (dimethoxyethane,tetrahydrofuran), alcohols (methanol, ethanol, etc.), aprotic polarsolvents (dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide, etc.), water and mixtures thereof.

The reaction temperature is generally about −100 to 200° C., preferablyabout −80 to 150° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr.

The aminating agent is preferably diphenylmethanimine. The amount of theaminating agent to be used is about 1 to 5 mol equivalent, preferablyabout 1 to 2 mol equivalent, per 1 mol of compound (XXXVI).

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, etc.). While the amount of the acid tobe used varies depending on the kind of solvent and the other reactioncondition, it is generally about 0.1 mol equivalent or more, per 1 molof compound (XXXVI). The solvent is THF or water. The reactiontemperature is about −20 to 100° C., preferably about 0 to 30° C., andthe reaction time is generally about 0.1 to 100 hr, preferably about 0.1to 24 hr.

The amounts of the hydroxyamine hydrochloride and sodium acetate to beused are about 1 to 5 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (XXXVI), respectively.

The solvent used for the treatment with hydroxyamine hydrochloride andsodium acetate is methanol. The reaction temperature is about −20 to100° C., preferably about 0 to 30° C., and the reaction time isgenerally about 1 to 100 hr, preferably about 1 to 72 hr.

(Step 8) This step is a step of subjecting compound (XXXVIII)(2,2-dimethyl-1,3-dioxane-4,6-dione) to a dehydration condensation withacetone in the presence of a morpholine and acetic acid to producecompound (XXXIX).

Compound (XXXVIII) may be a commercially available product.

The amounts of the morpholine and acetic acid to be used are about 0.01to 1 mol equivalent, preferably about 0.01 to 0.05 mol equivalent, per 1mol of compound (XXXVIII), respectively.

The amount of the acetone to be used is about 1 to 100 mol equivalent,per 1 mol of compound (XXXVIII). Acetone may be used as a solvent.

The reaction temperature is generally about 0 to 80° C., preferablyabout 0 to 50° C., and the reaction time is generally about 0.5 to 48hr, preferably 1 to 24 hr.

(Step 9)

This step is a step of converting compound (XXXVII) to Grignard reagent(XXXVIIa), and then coupling Grignard reagent (XXXVIIa) with compound(XXXIX) to produce compound (XL).

Compound (XXXVII) may be a commercially available product.

The step of the conversion of compound (XXXVII) to Grignard reagent(XXXVIIa) can be carried out by reacting compound (XXXVII) withisopropylmagnesium chloride.

Isopropylmagnesium chloride may be a commercially available product. Theamount thereof to be used is about 1 to 2 mol equivalent, preferablyabout 1 to 1.2 mol equivalent, per 1 mol of compound (XXXVII).

This reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.) and the like, and they may be mixed asappropriate.

The reaction temperature is generally about −80 to 30° C., preferablyabout −50 to 0° C., and the reaction time is generally about 0.5 to 4hr, preferably 0.5 to 2 hr.

The coupling reaction with compound (XXXIX) can be carried out withoutisolation of Grignard reagent (XXXVIIa).

In the coupling reaction with compound (XXXIX), the amount of thecompound (XXXIX) to be used is about 1 to 2 mol equivalent, preferablyabout 1 to 1.2 mol equivalent, per 1 mol of Grignard reagent (XXXVIIa).

This reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent include thosesimilar to the solvent used in the conversion of compound (XXXVII) toGrignard reagent (XXXVIIa).

The reaction temperature is generally about −80 to 30° C., preferablyabout −50 to 0° C., and the reaction time is generally about 0.5 to 8hr, preferably 0.5 to 5 hr.

(Step 10)

This step is a step of treating compound (XL) with hydrochloric acid toproduce compound (XLI) or a salt thereof.

The amount of the hydrochloric acid to be used is about 1 to 50 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (XL).

This reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent include ethers(diethyl ether, tetrahydrofuran, dioxane, etc.), alcohols (methanol,ethanol, 2-propanol, etc.), nitriles (acetonitrile, butyronitrile,etc.), amides (dimethylformamide, dimethylacetamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), water and the like, and they may be mixed asappropriate.

The reaction temperature is generally about 0 to 150° C., preferablyabout 20 to 120° C., and the reaction time is generally about 0.5 to 48hr, preferably 1 to 36 hr.

(Step 11)

This step is a step of treating compound (XLI) or a salt thereof withpolyphosphoric acid to produce compound (XLII).

The amount of the polyphosphoric acid to be used is about 1 to 50-foldweight, preferably about 1 to 10-fold weight, relative to compound(XLI).

The reaction temperature is generally about 20 to 150° C., preferablyabout 50 to 120° C., and the reaction time is generally about 0.5 to 24hr, preferably 0.5 to 10 hr.

(Step 12)

This step is a step of treating compound (XLII) with triethylsilane intrifluoroacetic acid to produce compound (XLIII).

The amount of the triethylsilane to be used is about 1 to molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (XLII).

The reaction temperature is generally about −20 to 100° C., preferablyabout 0 to 50° C., and the reaction time is generally about 0.5 to 100hr, preferably 1 to 50 hr.

(Step 13)

This step is a step of subjecting compound (XLIII) to an aminationreaction to produce compound (XIIb) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 7 of Method G1.

[Method H]

When compound (XII) is a compound represented by the formula:

(hereinafter to be referred to as compound (XIIc)) or a salt thereof,this compound can be produced according to Method H.

wherein PMB is a 4-methoxybenzyl group.

(Step 1)

This step is a step of subjecting compound (XLIV) or a salt thereof to amethyl esterification to produce compound (XLV).

Compound (XLIV) or a salt thereof may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

This reaction can be carried out according a method known per se (e.g.,the method described in “Protective Groups in Organic Synthesis, 3rdEd”, Wiley-Interscience, Inc. (1999) (Theodora W. Greene, Peter G. M.Wuts)). For example, compound (XLV) can be carried out by heatingcompound (XLIV) or a salt thereof in methanol in the presence of an acidcatalyst.

Examples of the acid catalyst used for this reaction include mineralacids (hydrochloric acid, sulfuric acid, etc.) organic sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids (boronfluoride etherate, etc.), thionyl chloride and the like. While theamount of the acid to be used varies depending on the kind of solventand the other reaction condition, it is generally about 0.0001 to 10 molequivalent, preferably about 0.01 to 0.1 mol equivalent, per 1 mol ofcompound (XLIV).

In this reaction, methanol can be used as a solvent. The reactiontemperature is, for example, within about 0 to 120° C., preferably about25 to 80° C., and the reaction time is, for example, about 0.5 to 100hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (XLV) to a methylation toproduce compound (XLVI).

In this reaction, compound (XLVI) can be obtained by treating compound(XLV) with iodomethane in the presence of a base.

Examples of the base used for this reaction include alkali metalhydrides (e.g., sodium hydride, lithium hydride). While the amount ofthe base to be used varies depending on the kind of solvent and theother reaction condition, it is generally about 2 to 10 mol equivalent,preferably about 2 to 5 mol equivalent, per 1 mol of compound (XLV).

The amount of the iodomethane to be used is generally about 2 to 10 molequivalent, preferably about 2 to 3 mol equivalent, per 1 mol ofcompound (XLV).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (dimethylformamide, etc.), sulfoxides (dimethylsulfoxide, etc.) and the like. These solvents may be used in a mixtureof two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −75 to 100° C.,preferably about −10 to 30° C. While the reaction time varies dependingon the reaction temperature and the like, it is, for example, about 0.5to 100 hr, preferably about 0.5 to 24 hr.

(Step 3)

This step is a step of subjecting compound (XLVI) to a catalytichydrogenation reaction using a transition metal catalyst to producecompound (XLVIII) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 2 of Method F.

(Step 4)

This step is a step of reacting compound (XLVIII) or a salt thereof withα-chloro-4-methoxytoluene in the presence of a base to produce compound(XLIX).

Examples of the base used for this reaction include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. While the amount of the base to be used variesdepending on the kind of, solvent and the other reaction condition, itis generally about 2 to 10 mol equivalent, preferably about 2 to 5 molequivalent, per 1 mol of compound (XLVIII).

The amount of the α-chloro-4-methoxytoluene to be used is about 2 to 10mol equivalent, preferably about 2 to 5 mol equivalent, per 1 mol ofcompound (XLVIII).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.), amides (N,N-dimethylformamide, etc.) and thelike. These solvents may be used in a mixture of two or more kindsthereof in an appropriate ratio.

The reaction temperature is, for example, within about −100 to 150° C.,preferably about −78 to 50° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

This reaction can also be carried out under the condition described inthe “when the amino group is protected by a PMB group” in Step 5 ofMethod B.

(Step 5)

This step is a step of treating compound (XLIX) with a reducing agent toproduce compound (L).

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., lithium borohydride, diisobutylaluminium hydride,aluminium hydride, lithium aluminium hydride). The amount of the metalhydride to be used is about 0.5 to 50 mol equivalent, per 1 mol ofcompound (XLIX).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane, etc.) and the like. These solvents may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is generally about −20 to 100° C., preferablyabout 0 to 30° C., and the reaction time is generally about 1 to 100 hr,preferably about 1 to 72 hr.

(Step 6)

This step is a step of subjecting compound (L) to a methylation reactionto produce compound (LI).

This step can be carried out in the same manner as in the methoddescribed in Step 8 of Method E.

(Step 7)

This step is a step of subjecting compound (LI) to a deprotectionreaction to produce compound (XIII) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 8 of Method B.

[Method I]

When compound (III) is a compound represented by the formula:

(hereinafter to be referred to as compound (IIIb)) or a salt thereof,this compound can be produced according to Method I.

wherein TBDPSO is a tert-butyldiphenylsilyloxy group.

(Step 1)

This step is a step of subjecting compound (LII) to hydrolysis using abase to convert compound (LII) to compound (LIII) or a salt thereof.

Compound (LII) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the base used for this reaction include inorganic bases(alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,potassium hydroxide and the like, alkoxides such as sodium methoxide,sodium ethoxide and the like, etc.) and the like. Among them, sodiumhydroxide is preferable. While the amount of the base to be used variesdepending on the kind of solvent and the other reaction condition, it isgenerally about 1 to 3 mol equivalent, preferably about 1 to 1.5 molequivalent, per 1 mol of compound (LII).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, t-butanol, etc.), hydrocarbons (benzene, toluene, xylene,hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.) or water and the like. Among them, ethanol andwater are preferable. These solvents may be used in a mixture of two ormore kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 100° C.,preferably about 0 to 30° C. While the reaction time varies depending onthe kind of compound (LII) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 24 hr, preferably about0.5 to 4 hr.

(Step 2)

This step is a step of subjecting compound (LIII) or a salt thereof to areduction reaction, and then protecting the resulting compound by aTBDMS (tert-butyldimethylsilyl) group to convert compound (LIII) or asalt thereof to compound (LIV).

The reduction reaction can be carried out in the same manner as in themethod described in Step 3 of Method B.

The protection reaction of the product obtained in the reductionreaction by a TBDMS group can be carried out by reacting compound (LIII)or a salt thereof with tert-butylchlorodiphenylsilane in the presence ofimidazole in a solvent that does not adversely influence the reaction.

The amounts of the imidazole and tert-butylchlorodiphenylsilane used forthis reaction to be used are about 1 to 5 mol equivalent, per 1 mol ofcompound (LIII), respectively.

Examples of the solvent that does not adversely influence the reactioninclude hydrocarbons (benzene, toluene, etc.), ethers (diethyl ether,dioxane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.),halogenated hydrocarbons (chloroform, dichloromethane, etc.), aproticpolar solvents (dimethylformamide, dimethylsulfoxide, etc.) and thelike, and they may be mixed as appropriate.

The reaction temperature is generally about −30 to 100° C., preferablyabout 0 to 30° C., and the reaction time is generally about 0.5 to 24hr, preferably 0.5 to 10 hr.

(Step 3)

This step is a step of subjecting compound (LIV) to a reduction reactionto produce compound (LV).

The reduction reaction can be carried out in the same manner as in themethod described in Step 3 of Method B.

(Step 4)

This step is a step of subjecting compound (LV) to a mesylation reactionto convert compound (LV) to a compound represented by the formula:

wherein MsO is a methylsulfonyloxy group (hereinafter to be referred toas compound (LVa)), and then reacting compound (LVa) with metal cyanideto produce compound (LVI).

The mesylation reaction can be carried out in the same manner as in themethod described in Step 5 of Method D.

Examples of the metal cyanide used for the reaction of compound (LVa)with metal cyanide include sodium cyanide, potassium cyanide and thelike. The amount thereof to be used is about 1 to 5 mol equivalent, per1 mol of compound (LVa).

This reaction is carried out in a solvent inert to the reaction.Examples of the solvent include hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,chloroform and the like; ethers such as diethyl ether, dioxane,tetrahydrofuran and the like; esters such as ethyl acetate and the like;amides such as N,N-dimethylformamide and the like, and mixtures thereof.

The reaction temperature is generally about 0° C. to 150° C., preferablyabout 20° C. to 100° C., and the reaction time is generally about 5 minto 72 hr, preferably about 0.5 hr to 40 hr.

(Step 5)

This step is a step of subjecting compound (LVI) to hydrolysis toconvert compound (LVI) to compound (LVII) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method B.

(Step 6)

This step is a step of reacting compound (LVII) or a salt thereof withbenzyl bromide in the presence of potassium carbonate to producecompound (LVIII).

The amounts of the potassium carbonate and benzyl bromide to be used areabout 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (LVII), respectively.

This reaction is carried out in a solvent inert to the reaction.Examples of the solvent include hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,chloroform and the like; ethers such as diethyl ether, dioxane,tetrahydrofuran and the like; esters such as ethyl acetate and the like;amides such as N,N-dimethylformamide and the like, and mixtures thereof.

The reaction temperature is generally about 0° C. to 100° C., preferablyabout 0° C. to 30° C., and the reaction time is generally about 0.5 hrto 24 hr, preferably about 0.5 hr to 14 hr.

(Step 7)

This step is a step of subjecting compound (LVIII) to an oxidationreaction to produce compound (IIIb) or a salt thereof.

Examples of the oxidizing agent to be used for the oxidation reactioninclude a mixture of sodium metaperiodate and ruthenium(IV) oxide. Theamount of the sodium metaperiodate to be used is about 1 to about 10 molequivalent, per 1 mol of compound (LVIII). The amount of theruthenium(IV) oxide to be used is about 0.01 to about 0.5 molequivalent, per 1 mol of compound (LVIII).

The oxidation reaction is carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includenitriles (e.g., acetonitrile), hydrocarbons (e.g., benzene, toluene,xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform),ethers (e.g., diethyl ether, dioxane, tetrahydrofuran), ketones (e.g.,acetone), water and mixtures thereof.

The reaction temperature is generally about −20° C. to 50° C.,preferably about 0° C. to 30° C., and the reaction time is generallyabout 0.5 hr to 24 hr, preferably about 0.5 hr to 4 hr.

[Method J]

When compound (III) is a compound represented by the formula:

(hereinafter to be referred to as compound (IIIc)) or a salt thereof,this compound can be produced according to Method J.

wherein TsO is a p-toluenesulfonyloxy group.

(Step 1)

This step is a step of subjecting compound (LIX) to a tosylationreaction to produce compound (LX).

Compound (LIX) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

The tosylation reaction can be carried out in the presence of a base anda tosylating agent.

The kinds and amounts of the base and solvent used for the tosylationreaction, the reaction temperature and the reaction time are the same asin Step 1 of Method D.

Examples of the tosylating agent include p-toluenesulfonyl chloride andthe like. While the amount of the tosylating agent to be used variesdepending on the kind of solvent and the other reaction condition, it isgenerally 1 about 1 to 10 mol equivalent, preferably about 1 to 5 molequivalent, per 1 mol of compound (LIX).

(Step 2)

This step is a step of treating compound (LX) with a base to producecompound (LXI).

Examples of the base to be used in this step include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.) and the like. Among them, sodium methoxideis preferable. While the amount of the base to be used varies dependingon the kind of solvent and the other reaction condition, it is generallyabout 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent,per 1 mol of compound (LX).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.), alcohols(methanol, ethanol, etc.), aliphatic hydrocarbons (hexane, heptane,etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.),ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles(acetonitrile, etc.), esters (ethyl acetate, etc.), amides(dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.) and thelike. These solvents may be used in a mixture of two or more kindsthereof in an appropriate ratio.

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (LX),the reaction temperature and the like, it is, for example, about 0.5 to24 hr, preferably about 0.5 to 4 hr.

(Step 3)

This step is a step of treating compound (LXI) withlithiumdiisopropylamide (LDA) to produce compound (LXII).

The amount of the LDA is about 1 to 5 mol equivalent, preferably about 1to 2 mol equivalent, per 1 mol of compound (LXI).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include hydrocarbons(benzene, toluene, etc.), ethers (diethyl ether, dioxane,tetrahydrofuran, etc.), halogenated hydrocarbons (chloroform,dichloromethane, etc.), amides (N,N-dimethylformamide, etc.) and thelike, and they may be mixed as appropriate.

The reaction temperature is generally about −80 to 30° C., preferablyabout −80 to 10° C., and the reaction time is generally about 0.5 to 24hr, preferably 0.5 to 4 hr.

(Step 4)

This step is a step of subjecting compound (LXII) to a protection by abenzyl group to produce compound (LXIII).

This reaction can be carried out in the same manner as in the methoddescribed in the “when the amino group is protected by a Bn group” inStep 5 of Method

In addition, tetra-n-butylammonium iodide may be used as an additive forthe progress of the reaction. The amount thereof to be used is about0.01 to 1 mol equivalent, preferably about 0.05 to 0.5 mol equivalent,per 1 mol of compound (LXII).

(Step 5)

This step is a step of subjecting compound (LXIII) to a reductionreaction to convert compound (LXIII) to compound (LXIV).

The reduction reaction can be carried out in the same manner as in themethod described in Step 3 of Method B.

(Step 6)

This step is a step of subjecting compound (LXIV) to a mesylationreaction to convert compound (LXIV) to a compound represented by theformula:

wherein MsO is a methylsulfonyloxy group (hereinafter to be referred toas compound (LXIVa)), and then reacting compound (LXIVa) with metalcyanide to produce compound (LXV).

This step can be carried out in the same manner as in the methoddescribed in Step 4 of Method I.

(Step 7)

This step is a step of subjecting compound (LXV) to hydrolysis toconvert compound (LXV) to compound (LXVI) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method B.

(Step 8)

This step is a step of subjecting compound (LXVI) or a salt thereof to adeprotection reaction to produce compound (LXVII) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in the “deprotection reaction employing catalytichydrogenation reaction” in Step 8 of Method B.

(Step 9)

This step is a step of reacting compound (LXVII) or a salt thereof withbenzyl bromide in the presence of potassium carbonate to producecompound (LXVIII).

This step can be carried out in the same manner as in the methoddescribed in Step 6 of Method I.

(Step 10)

This step is a step of subjecting compound (LXVIII) to an oxidationreaction to produce compound (IIIc) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in Step 7 of Method I.

[Method K]

When compound (III) is a compound represented by the formula:

(hereinafter to be referred to as compound (IIId)) or a salt thereof,this compound can be produced according to Method K.

(Step 1)

This step is a step of reacting compound (LXIX) or a salt thereof withtert-butyl triphenylphosphoranylideneacetate to produce compound (LXX)or a salt thereof.

Compound (LXIX) or a salt thereof and tert-butyltriphenylphosphoranylideneacetate may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

The amount of the tert-butyl triphenylphosphoranylidenacetate to be usedis about 1 to about 5 mol equivalent, per 1 mol of compound (LXIX).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include nitriles (e.g.,acetonitrile), hydrocarbons (e.g., benzene, toluene, xylene),halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers(e.g., diethyl ether, dioxane, tetrahydrofuran) and mixtures thereof.

The reaction temperature is generally about −20° C. to 150° C.,preferably about 10° C. to 100° C., and the reaction time is generallyabout 0.5 hr to 24 hr, preferably about 0.5 hr to 14 hr.

(Step 2)

This step is a step of subjecting compound (LXX) or a salt thereof to areduction reaction to produce compound (LXXI) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in the “method employing a catalytic hydrogenation reaction”in Step 3 of Method B.

(Step 3)

This step is a step of reacting compound (LXXI) or a salt thereof with(R)-1-phenylethanol in the presence of DEAD and triphenylphosphine toproduce compound (LXXII).

In this step, two stereoisomers are produced, and subjected to chiralcolumn chromatography to give compound (LXXII).

The amounts of the DEAD, triphenylphosphine and (R)-1-phenylethanol usedfor this reaction to be used are about 1 to mol equivalent, preferablyabout 1 to 2 mol equivalent, per 1 mol of compound (LXXI), respectively.

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include nitriles (e.g.,acetonitrile), hydrocarbons (e.g., benzene, toluene, xylene),halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers(e.g., diethyl ether, dioxane, tetrahydrofuran) and mixtures thereof.

The reaction temperature is generally about −20° C. to 150° C.,preferably about 10° C. to 100° C., and the reaction time is generallyabout 0.5 hr to 24 hr, preferably about 0.5 hr to 14 hr.

(Step 4)

This step is a step of subjecting compound (LXXII) to a deprotectionreaction to produce compound (IIId) or a salt thereof.

This step can be carried out in the same manner as in the methoddescribed in the “deprotection reaction employing catalytichydrogenation reaction” in Step 8 of Method B.

[Method L]

When compound (III) is a compound represented by the formula:

(hereinafter to be referred to as compound (IIIe)) or a salt thereof, ora compound represented by the

(hereinafter to be referred to as compound (IIIf)) or a salt thereof,this compound can be produced according to Method L.

(Step 1)

This step is a step of reacting compound (LXXIII) or a salt thereof withbenzyl bromide in the presence of potassium carbonate to producecompound (LXXIV) and compound (LXXV).

Compound (LXXIII) or a salt thereof may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto. This step can be carried out in the samemanner as in the method described in Step 6 of Method I.

Compound (LXXIV) and compound (LXXV) can be each isolated by separationand purification using silica gel chromatography.

(Step 2)

This step is a step of subjecting compound (LXXIV) or compound (LXXV) toa deprotection reaction to produce compound (IIIe) or a salt thereof, orcompound (IIIf) or a salt thereof, respectively.

This step can be carried out in the same manner as in the methoddescribed in the “deprotection reaction employing catalytichydrogenation reaction” in Step 8 of Method B.

In each reaction for the production of the objective compound and theraw material compound, when the raw material compound has an aminogroup, a carboxyl group or a hydroxy group, these groups may beprotected by a protecting group generally used in peptide chemistry andthe like. By removing the protecting group as necessary after thereaction, the objective compound can be obtained.

Examples of the protecting group include those described in “ProtectiveGroups in Organic Synthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999)(Theodora W. Greene, Peter G. M. Wuts)

Examples of the amino-protecting group include a formyl group, C₁₋₆alkyl-carbonyl groups (e.g., acetyl, propionyl groups, etc.), aphenylcarbonyl group, C₁₋₆ alkyl-oxycarbonyl groups (e.g.,methoxycarbonyl, ethoxycarbonyl groups, etc.), aryloxycarbonyl groups(e.g., a phenyloxycarbonyl group, etc.), C₇₋₁₀ aralkyl-carbonyl groups(e.g., a benzyloxycarbonyl group, etc.), a benzyl group, a benzhydrylgroup, a trityl group, a phthaloyl group and the like. These protectinggroups optionally have substituent(s). Examples of the substituentinclude halogen atoms (e.g., fluorine, chlorine, bromine, iodine atoms),C₁₋₆ alkyl-carbonyl groups (e.g., acetyl, propionyl, butylcarbonylgroups, etc.), a nitro group and the like. The number of the substituentis 1 to 3.

Examples of the carboxyl-protecting group include C₁₋₆ alkyl groups(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl groups,etc.), a phenyl group, a trityl group, a silyl group and the like. Theseprotecting groups optionally have substituent(s). Examples of thesubstituent include halogen atoms (fluorine, chlorine, bromine, iodineatoms), a formyl group, C₁₋₆ alkyl-carbonyl groups (e.g., acetyl,propionyl, butylcarbonyl groups, etc.), a nitro group and the like. Thenumber of the substituent is 1 to 3.

Examples of the hydroxyl-protecting group include C₁₋₆ alkyl groups(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl groups,etc.), a phenyl group, C₇₋₁₀ aralkyl groups (e.g., a benzyl group,etc.), a formyl group, C₁₋₆ alkyl-carbonyl groups (e.g., acetyl,propionyl groups, etc.), aryloxycarbonyl groups (e.g., aphenyloxycarbonyl group, etc.), C₇₋₁₀ aralkyl-carbonyl groups (e.g., abenzyloxycarbonyl group, etc.), a pyranyl group, a furanyl group, asilyl group and the like. These protecting groups optionally havesubstituent(s). Examples of the substituent include halogen atoms(fluorine, chlorine, bromine, iodine atoms), C₁₋₆ alkyl groups, a phenylgroup, C₇₋₁₀ aralkyl groups, a nitro group and the like. The number ofthe substituent is 1 to 4.

The removal of the protecting group can be carried out according to amethod known per se, for example, the method described in “ProtectiveGroups in Organic Synthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999)(Theodora W. Greene, Peter G. M. Wuts) and the like, or a methodanalogous thereto. For example, a method treating with an acid, a base,reduction, ultraviolet radiation, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like can be employed.

When the object product is obtained in a free form by theabove-mentioned reaction, it may be converted to a salt by aconventional method. When it is obtained as a salt, it can also beconverted to a free form or other salt by a conventional method. Thethus-obtained compound (I) can be isolated and purified from thereaction solution by a known 0.25 means, for example, phase transfer,concentration, solvent extraction, fractionation, crystallization,recrystallization, chromatography and the like.

When compound (I) contains an isomer such as a tautomer, an opticalisomer, a stereoisomer, a regioisomer, a rotamer and the like, anyisomer and a mixture thereof are also encompassed in the compound of thepresent invention. Furthermore, when compound (I) contains an opticalisomer, an optical isomer resolved from racemate compound is alsoencompassed in compound (I).

The optical isomer can be produced according to a method known per se.Specifically, the optical isomer is obtained using an optically activesynthetic intermediate or by subjecting the racemic final product to anoptical resolution according to a known method.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method etc.

1) Fractional Recrystallization Method

A method wherein a salt of a racemate with an optically active compound(e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column (achiral column) for separation of an optical isomer to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Chemical Industries, Ltd.) and the like, and developed withwater, various buffers (e.g., phosphate buffer, etc.) and organicsolvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine, etc.) as an eluent, solely or inadmixture to separate the optical isomer. In the case of a gaschromatography, for example, a chiral column such as CP-Chirasil-DeX CB(manufactured by GL Sciences Inc.) and the like is used to allowseparation.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallization method, a chromatography method etc.) andthe like, and is subjected to a chemical treatment such as hydrolysisand the like to separate an optically active reagent moiety, whereby anoptical isomer is obtained. For example, when compound (I) containshydroxy or primary or secondary amino in a molecule, the compound and anoptically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxyl group, the compound and an opticallyactive amine or an optically active alcohol reagent are subjected tocondensation reaction to give diastereomers of the amide compound or theester compound, respectively. The separated diastereomer is converted toan optical isomer of the original compound by acid hydrolysis or basehydrolysis.

Compound (I) may be a crystal. Even if compound (I) is in a singlecrystal form or mixed crystal form, it is encompassed in compound (I).

Compound (I) may be a pharmaceutically acceptable cocrystal or a saltthereof. The cocrystal or a salt thereof means a crystalline substanceconstituted with two or more special solids at room temperature, eachhaving different physical properties (e.g., structure, melting point,melting heat, hygroscopicity, solubility and stability etc.). Thecocrystal or a salt thereof can be produced according to acocrystallization method known per se.

The crystal of compound (I) can be produced according to acrystallization method known per se.

Examples of the crystallization method include crystallization methodfrom a solution, crystallization method from vapor, crystallizationmethod from a melt, and the like.

The “crystallization method from a solution” is typically a method ofshifting a non-saturated state to supersaturated state by varyingfactors involved in solubility of compounds (solvent composition, pH,temperature, ionic strength, redox state, etc.) or the amount ofsolvent. Specific examples thereof include a concentration method, aslow cooling method, a reaction method (a diffusion method, anelectrolysis method), a hydrothermal growth method, a flux method andthe like. Examples of the solvent to be used include aromatichydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, etc.), saturatedhydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g.,diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.),nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.),sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g.,N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),alcohols (e.g., methanol, ethanol, isopropanol, etc.), water and thelike. These solvents are used alone or in a combination of two or moreat a suitable ratio (e.g., 1:1 to 1:100 (a volume ratio)). Wherenecessary, a seed crystal can be used.

The “crystallization method from vapor” is, for example, a vaporizationmethod (a sealed tube method, a gas stream method), a gas phase reactionmethod, a chemical transportation method and the like.

The “crystallization method from a melt” is, for example, a normalfreezing method (a pulling method, a temperature gradient method, aBridgman method), a zone melting method (a zone leveling method, afloating zone method), a special growth method (a VLS method, a liquidphase epitaxy method) and the like.

Preferable examples of the crystallization method include a methodcomprising dissolving compound (I) in a suitable solvent (e.g., alcoholssuch as methanol, ethanol etc.) at 20° C. to 120° C., and cooling theobtained solution to a temperature (e.g., 0-50° C., preferably 0-20° C.)not higher than the dissolution temperature, and the like.

The thus-obtained crystals of the present invention can be isolated, forexample, by filtration and the like.

An analysis method of the obtained crystal is generally a method ofcrystal analysis by powder X-ray diffraction.

As a method of determining crystal orientation, a mechanical method oran optical method and the like can also be used.

In the present specification, the peak by powder X-RAY diffraction meansthe peak measured, for example, by RINT2100 (Rigaku Corporation) and thelike using Cu-Kα1-ray (tube voltage: 40 KV; tube current: 50 mA) as asource.

Generally, the peaks by melting point and powder X-RAY diffraction mayvary depending on measurement equipment, measurement condition and thelike. The crystal in the present specification may show peaks differentfrom those by melting point or powder X-RAY diffraction described in thepresent specification as long as they are within general error range.

The crystal of compound (I) obtained by the above-mentioned productionmethod (hereinafter to be referred to as “the crystal of the presentinvention”) has high purity, high quality, and low hygroscopicity, isnot denatured even after a long-term preservation under generalconditions, and is extremely superior in the stability. In addition, itis also superior in the biological properties (e.g., pharmacokinetics(absorption, distribution, metabolism, excretion), efficacy expressionetc.) and is extremely useful as a medicament.

In the present specification, the specific optical rotation ([α]_(D))means a specific optical rotation measured, for example, by polarimeter(JASCO), P-1030 polarimeter (No.AP-2)) and the like.

In the present specification, the melting point means a melting pointmeasured, for example, by micro melting point apparatus (Yanako,MP-500D), DSC (differential scanning calorimetry analysis) apparatus(SEIKO, EXSTAR6000) and the like.

Compound (I) may be a solvate (e.g., a hydrate (e.g., hemihydrate,monohydrate, dihydrate etc.)) or a non-solvate (e.g., non-hydrate,etc.), and they are also encompassed in compound (I).

Compound (I) may be labeled or substituted with an isotope (e.g., ²H,³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, or ¹²⁵I), and they are also encompassed incompound (I). Compound (I) labeled or substituted with an isotope can beused, for example, as a tracer (PET tracer) used for positron emissiontomography (PET), and is useful in the field such as medical diagnosisand the like.

The prodrug of compound (I) means a compound which can be converted intocompound (I) by reaction with an enzyme, gastric acid, or the like underphysiological conditions in the living body. In other words, it means acompound which can be converted into compound (I) by enzymaticoxidation, reduction, hydrolysis or the like, or a compound which can beconverted into compound (I) by hydrolysis with gastric acid or the like.Examples of the prodrug of compound (I) include a compound in whichamino of compound (I) is acylated, alkylated or phosphorylated (e.g.,the amino of compound (I) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated ortert-butylated); a compound in which hydroxyl of compound (I) isacylated, alkylated, phosphorylated or borated (e.g., hydroxyl ofcompound (I) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated); a compound in which carboxy ofcompound (I) is esterified or amidated (e.g., a compound in whichcarboxy of compound (I) is ethyl esterified, phenyl esterified,carboxymethyl esterified, dimethylaminomethyl esterified,pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified,phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified, cyclohexyloxycarbonylethyl esterified or methylamidated).These compounds can be produced from compound (I) by a method known perse. The prodrug of compound (I) may be a compound that converts tocompound (I) under physiological conditions as described in Developmentof Pharmaceutical Products, vol. 7, Molecule Design, 163-198, HirokawaShoten (1990).

Since compound (I) and a prodrug thereof [hereinafter sometimes to beabbreviated as the compound of the present invention] show superiorRORγt inhibitory activity, they are useful as safe medicaments based onsuch action.

For example, the medicament of the present invention containing thecompound of the present invention can be used for a mammal (e.g., mouse,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as aprophylactic or therapeutic agent for RORγt associated diseases, Th17cell associated diseases and IL-17A or IL-17F associated diseases, morespecifically, the diseases described in (1)-(4) below.

(1) inflammatory diseases (e.g., rheumatoid arthritis, acutepancreatitis, chronic pancreatitis, asthma, bronchial asthma, adultrespiratory distress syndrome, chronic obstructive pulmonary disease(COPD), inflammatory bone disease, inflammatory pulmonary disease,inflammatory bowel disease, celiac disease, Behcet's disease, hepatitis,alcoholic liver fibrosis, alcoholic hepatitis, alcoholic cirrhosis,hepatitis B viral liver disorder, primary biliary cirrhosis (PBC),primary sclerosing cholangitis (PSC), transient ischemic attack (TIA),systemic inflammatory response syndrome (SIRS), dry eye, glaucoma,uveitis, orbital cellulitis, sudden orbital inflammation, age-relatedmacular degeneration, postoperative or posttraumatic inflammation, liverdisorder, pneumonia, nephritis, meningitis, cystitis,pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis,dermatitis, chronic pneumonia, bronchitis, pulmonary infarction,silicosis, pulmonary sarcoidosis, autoimmune anemia, Goodpasture'ssyndrome, Graves' disease, Hashimoto's thyroiditis, vasculitis, Basedowdisease, sinusitis, allergic rhinitis, chronic hypertrophic rhinitisetc.),(2) autoimmune diseases (e.g., rheumatoid arthritis, ankylosingspondylitis, psoriasis, multiple sclerosis (MS), polymyositis,neuromyelitis optica (NMO), chronic inflammatory demyelinatingpolyneuropathy (CIDP), dermatomyositis (DM), polyarteritis nodosa (PN),mixed connective tissue disease (MCTD), amyotrophic lateral sclerosis(ALS), Guillain-Barre syndrome, myasthenia gravis, Parkinson's disease,spinal muscular atrophy, spinal cerebellar atrophy, progressivesupranuclea palsy, Fisher syndrome, central nervous lupus, acutedisseminated encephalomyelitis, multiple system atrophy, Huntington'sdisease, Alzheimer's disease, cerebrovascular dementia, diffuse Lewybody disease, cerebrovascular disorder, cerebral infarction, transientischemic attack, intracerebral hemorrhage, vascular disease of spinalcord, spinal cord infarction, polyneuropathy, Lambert-Eaton syndrome,muscular dystrophy, metabolic myopathy, inflammatory myopathy, inclusionbody myositis, encephalitis, meningitis, Sjogren's syndrome, systemiclupus erythematosus, scleroderma, pemphigus, profundus lupuserythematosus, chronic thyroiditis, Graves' disease, autoimmunegastritis, type I and type II diabetes, autoimmune hemolytic anemia,autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronicactive hepatitis, myasthenia gravis, inflammatory bowel disease (IBD),ulcerative colitis (UC), Crohn's disease, graft versus host disease,Addison's disease, abnormal immunoresponse, arthritis, dermatitis,radiodermatitis, sarcoidosis, type I diabetes etc.),(3) bone or joint degenerative diseases (e.g., rheumatoid arthritis,osteoporosis, osteoarthritis etc.),(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma,infantile hemangioma, multiple myeloma, acute myeloblastic leukemia,chronic sarcoma, multiple myeloma, chronic myelogenous leukemia,metastasis melanoma, Kaposi's sacroma, vascular proliferation, cachexia,metastasis of the breast cancer, cancer (e.g., colorectal cancer (e.g.,familial colorectal cancer, hereditary nonpolyposis colorectal cancer,gastrointestinal stromal tumor and the like), lung cancer (e.g.,non-small cell lung cancer, small cell lung cancer, malignantmesothelioma and the like), mesothelioma, pancreatic cancer (e.g.,pancreatic duct cancer and the like), gastric cancer (e.g., papillaryadenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma and thelike), breast cancer (e.g., invasive ductal carcinoma, ductal carcinomain situ, inflammatory breast cancer and the like), ovarian cancer (e.g.,ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germcell tumor, ovarian low malignant potential tumor and the like),prostate cancer (e.g., hormone-dependent prostate cancer, non-hormonedependent prostate cancer and the like), liver cancer (e.g., primaryliver cancer, extrahepatic bile duct cancer and the like), thyroidcancer (e.g., medullary thyroid carcinoma and the like), kidney cancer(e.g., renal cell carcinoma, transitional cell carcinoma in kidney andurinary duct and the like), uterine cancer, endometrial cancer, braintumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuseastrocytoma, anaplastic astrocytoma and the like), melanoma (melanoma),sarcoma, urinary bladder cancer, hematologic cancer and the likeincluding multiple myeloma, hypophyseal adenoma, glioma, acousticneurinoma, retinoblastoma, head and neck cancer, pharyngeal cancer,laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer,duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreaticendocrine tumor, cancer of the bile duct, gallbladder cancer, penilecancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer,endometrial cancer, uterus sarcoma, cholionic disease, vaginal cancer,skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma,malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, acutelymphocytic leukemia, chronic lymphocytic leukemia, adult T cellleukemia, chronic bone marrow proliferative disease, pancreaticendocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,cancer of unknown primary].

The medicament of the present invention can be preferably used as anagent for the prophylaxis or treatment of psoriasis, inflammatory boweldisease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoidarthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE) and the like.

In another embodiment, the medicament of the present invention can bepreferably used as an agent for the prophylaxis or treatment ofautoimmune disease, inflammatory disease, bone or articular disease, orneoplastic disease, particularly preferably psoriasis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE), chronicobstructive pulmonary diseases, ovarian cancer, non small cell lungcancer, breast cancer, stomach cancer, head and neck cancer, prostatecancer or endometrial cancer.

Here, the above-mentioned “prophylaxis” of a disease means, for example,administration of a medicament containing the compound of the presentinvention to patients who are expected to have a high risk of the onsetdue to some factor relating to the disease but have not developed thedisease or patients who have developed the disease but do not have asubjective symptom, or administration of a medicament containing thecompound of the present invention to patients who are feared to showrecurrence of the disease after treatment of the disease.

The medicament of the present invention shows superior pharmacokinetics(e.g., a half-life of the drug in plasma), low toxicity (e.g., HERGinhibition, CYP inhibition, CYP induction), and decreased druginteraction. The compound of the present invention can be directly usedas a medicament, or as the medicament of the present invention byproducing a pharmaceutical composition by mixing with a pharmaceuticallyacceptable carrier by a means known per se and generally used in aproduction method of pharmaceutical preparations. The medicament of thepresent invention can be orally or parenterally administered safely tomammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats,hamsters, rabbits, cats, dogs, sheep and goats).

A medicament containing the compound of the present invention can besafely administered solely or by mixing with a pharmacologicallyacceptable carrier according to a method known per se (e.g., the methoddescribed in the Japanese Pharmacopoeia etc.) as the production methodof a pharmaceutical preparation, and in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal and intratumoradministrations, administration to the vicinity of tumor, and directadministration to the lesion).

The content of the compound of the present invention in the medicamentof the present invention is about 0.01 to 100% by weight of the entiremedicament. While the dose varies depending on the subject ofadministration, administration route, disease and the like, for example,for oral administration to an adult inflammatory bowel disease (IBD)patient (body weight about 60 kg), it is about 0.1 mg/kg body weight to30 mg/kg body weight, preferably about 1 mg/kg body weight to 20 mg/kgbody weight as an active ingredient (compound (I)) for one day, which isadministered once to several times, preferably once or two to threetimes.

The pharmaceutically acceptable carrier, which may be used for theproduction of the medicament of the present invention, may beexemplified by various organic or inorganic carrier materials that areconventionally used as preparation materials, for example, excipient,lubricant, binding agent and disintegrant for solid preparations; orsolvent, solubilizing agent, suspending agent, isotonic agent, bufferingagent, soothing agent and the like for liquid preparations. Furthermore,when necessary, ordinary additives such as preservative, antioxidant,colorant, sweetening agent, adsorbing agent, wetting agent and the likecan be also used as appropriate in an appropriate amount.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like. Examples of the binding agentinclude crystalline cellulose, white sugar, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose,carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such asphosphates, acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfites, ascorbic acid,α-tocopherol and the like.

For the prophylaxis or treatment of various diseases, the compound ofthe present invention can also be used together with other medicaments.In the following, a medicament to be used when the compound of thepresent invention is used together with other drug is referred to as“the combination agent of the present invention”.

For example, when the compound of the present invention is used as anRORγt inhibitor, Th17 cell inhibitor, IL-17A or IL-17F inhibitor, it canbe used in combination with the following drugs.

(1) Non-steroidal anti-inflammatory drug (NSAIDs)

(i) Classical NSAIDs

alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen,thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam,nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine,antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid,diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin,ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen,pranoprofen, floctafenine, piroxicam, epirizole, tiaramidehydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate,ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,allopurinol, sodium aurothiomalate, hyaluronate sodium, sodiumsalicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, oxymorphone or a saltthereof and the like.

(ii) Cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2selective inhibitor and the like)

salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib,valdecoxib, diclofenac, indomethacin, loxoprofen and the like.

(iii) Nitric oxide-releasing NSAIDs(2) disease-modifying anti-rheumatic drugs (DMARDs)(i) Gold preparation

auranofin and the like.

(ii) penicillamine

D-penicillamine.

(iii) aminosalicylic acid preparation

sulfasalazine, mesalazine, olsalazine, balsalazide, salazosulfapyridine.

(iv) antimalarial drug

chloroquine and the like.

(v) pyrimidine synthesis inhibitor

leflunomide and the like.

(vi) tacrolimus(3) anti-cytokine drug(I) protein drug(i) TNF inhibitor

etanercept, infliximab, adalimumab, certolizumab pegol, golimumab,PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-αantibody and the like.

(ii) interleukin-1 inhibitor

anakinra (interleukin-1 receptor antagonist), canakinumab, rilonacept,soluble interleukin-1 receptor and the like.

(iii) interleukin-6 inhibitor

tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6antibody and the like.

(iv) interleukin-10 drug

interleukin-10 and the like.

(v) interleukin-12/23 inhibitor

ustekinumab, briakinumab (anti-interleukin-12/23 antibody) and the like.

(vi) B cell activation inhibitor

rituxan, benrista, ocrelizumab and the like.

(vii) co-stimulatory molecules related protein drug abatacept and thelike.(II) non-protein drug(i) MAPK inhibitor

BMS-582949 and the like.

(ii) gene modulator

inhibitor of molecule involved in signal transduction, such as NF-κ,NF-κB, IKK-1, IKK-2, AP-1 and the like, and the like.

(iii) cytokine production inhibitor

iguratimod, tetomilast and the like.

(iv) TNF-α converting enzyme inhibitor(v) interleukin-1β converting enzyme inhibitor

belnacasan and the like.

(vi) interleukin-6 antagonist

HMPL-004 and the like.

(vii) interleukin-8 inhibitor

IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.

(viii) chemokine antagonist

CCR9 antagonist (vercirnon (vercirnon sodium), CCX025,N-{4-chloro-2-[(1-oxidepyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy)benzenesulfonamide),MCP-1 antagonist and the like.

(ix) interleukin-2 receptor antagonist

denileukin, diftitox and the like.

(x) therapeutic vaccines

TNF-α vaccine and the like.

(xi) gene therapy drug

gene therapy drugs aiming at promoting the expression of gene having ananti-inflammatory action such as interleukin-4, interleukin-10, solubleinterleukin-1 receptor, soluble TNF-α receptor and the like.

(xii) antisense compound

ISIS 104838, SMAD7 antisense oligonucleotide and the like.

(xiii) other antibody, biological preparation

Abciximab, basiliximab, cetuximab, brentuximab, daclizumab, palivizumab,trastuzumab, omalizumab, Efalizumab, bevacizumab, basiliximab,ranibizumab, eculizumab, mogamulizumab, ofatumumab, denosumab,ipilimumab, alefacept, romiplostim, belatacept, aflibercept and thelike.

(4) integrin inhibitor

natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.

(5) immunomodulator (immunosuppressant)

methotrexate, mizoribine, cyclophosphamide, MX-68, atiprimoddihydrochloride, abatacept, CKD-461, rimexolone, cyclosporine,tacrolimus, gusperimus, azathiopurine, antilymphocyte serum,freeze-dried sulfonated normal immunoglobulin, erythropoietin, colonystimulating factor, interleukin, interferon, cyclophosphamide,mycophenolate mofetil, immunoglobulin preparation for injection,fingolimod, S1P1 receptor agonist, dimethyl fumarate, copaxone,interferon β preparation, laquinimod, teriflunomide, and the like.

(6) proteasome inhibitor

velcade and the like.

(7) JAK inhibitor

tofacitinib and the like.

(8) steroid

dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone,fluorometholone, beclomethasone dipropionate, estriol and the like.

(9) angiotensin converting enzyme inhibitor

enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril andthe like.

(10) angiotensin II receptor antagonist

candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan andthe like.

(11) diuretic drug

hydrochlorothiazide, spironolactone, furosemide, indapamide,bendrofluazide, cyclopenthiazide and the like.

(12) cardiotonic drug

digoxin, dobutamine and the like.

(13) β receptor antagonist

carvedilol, metoprolol, atenolol and the like.

(14) Ca sensitizer

caldaret hydrate and the like.

(15) Ca channel antagonist

nifedipine, diltiazem, verapamil and the like.

(16) anti-platelet drug, anticoagulator

heparin, aspirin, warfarin and the like.

(17) HMG-CoA reductase inhibitor

atorvastatin, simvastatin and the like.

(18) contraceptive(i) sex hormone or derivatives thereof

gestagen or a derivative thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate,norethisterone, norethisterone enanthate, norethindrone, norethindroneacetate, norethynodrel, levonorgestrel, norgestrel, ethynodioldiacetate, desogestrel, norgestimate, gestodene, progestin,etonogestrel, drospirenone, dienogest, trimegestone, nestorone,chlormadinone acetate, mifepristone, nomegestrol acetate, tosagestin,TX-525, ethinylestradiol/TX525) or a combination agent of a gestagen ora derivative thereof and an estrogen or a derivative thereof (estradiol,estradiol benzoate, estradiol cypionate, estradiol dipropionate,estradiol enanthate, estradiol hexahydrobenzoate, estradiolphenylpropionate, estradiol undecanoate, estradiol valerate, estrone,ethinylestradiol, mestranol) and the like.

(ii) antiestrogen

ormeloxifene, mifepristone, Org-33628 and the like.

(iii) spermatocide

ushercell and the like.

(19) others(i) T cell inhibitors(ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor

mycophenolate mofetil and the like.

(iii) adhesion molecule inhibitor

alicaforsen sodium, selectin inhibitor, ELAM-1 inhibitor,

VCAM-1 inhibitor, ICAM-1 inhibitor and the like.(iv) thalidomide(v) cathepsin inhibitor(vi) matrix metalloprotease (MMPs) inhibitor

V-85546 and the like.

(vii) glucose-6-phosphate dehydrogenase inhibitor(viii) Dihydroorotate dehydrogenase (DHODH) inhibitor(ix) phosphodiesterase IV (PDE IV) inhibitor

roflumilast, apremilast, CG-1088 and the like.

(x) phospholipase A₂ inhibitor(xi) iNOS inhibitor

VAS-203 and the like.

(xii) microtubule stimulating drug

paclitaxel and the like.

(xiii) microtuble inhibitor

reumacon and the like.

(xiv) MHC class II antagonistxv) prostacyclin agonist

iloprost and the like.

(xvi) CD4 antagonist

zanolimumab and the like.

(xvii) CD23 antagonist(xviii) LTB4 receptor antagonist

DW-1350 and the like.

(xix) 5-lipoxygenase inhibitor

zileuton and the like.

(xx) cholinesterase inhibitor

galanthamine and the like.

(xxi) tyrosine kinase inhibitor

Tyk2 inhibitor (WO2010/142752) and the like.

(xxii) cathepsin B inhibitor(xxiii) adenosine deaminase inhibitor

pentostatin and the like.

(xxiv) osteogenesis stimulator(xxv) dipeptidylpeptidase inhibitor(xxvi) collagen agonist(xxvii) capsaicin cream(xxviii) hyaluronic acid derivative

synvisc (hylan G-F 20), orthovisc and the like.

(xxix) glucosamine sulfate(xxx) amiprilose(xxxi) CD-20 inhibitor

rituximab, ibritumomab, tositumomab, ofatumumab and the like.

(xxxii) BAFF inhibitor

belimumab, tabalumab, atacicept, blisibimod and the like.

(xxxiii) CD52 inhibitor

alemtuzumab and the like.

Other concomitant drugs besides the above-mentioned drug include, forexample, antibacterial agent, antifungal agent, antiprotozoal agent,antibiotic, antitussive and expectorant drug, sedative, anesthetic,antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug,anticoagulant, tranquilizer, antipsychotic, antitumor drug,hypolipidemic drug, muscle relaxant, antiepileptic drug, antidepressant,antiallergic drug, cardiac stimulants, therapeutic drug for arrhythmia,vasodilator, vasoconstrictor, therapeutic drug for diabetes,antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeuticagent for pollakisuria/anischuria, therapeutic agent for atopicdermatitis, therapeutic agent for allergic rhinitis, hypertensor,endotoxin-antagonist or -antibody, signal transduction inhibitor,inhibitor of inflammatory mediator activity, antibody to inhibitinflammatory mediator activity, inhibitor of anti-inflammatory mediatoractivity, antibody to inhibit anti-inflammatory mediator activity andthe like. Specific examples thereof include the following.

(1) Antibacterial agent(i) sulfa drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine,silver sulfadiazine and the like.

(ii) Quinolone antibacterial agent

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

(iii) antiphthisic

isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

(iv) antiacidfast bacterium drug

diaphenylsulfone, rifampicin and the like.

(v) antiviral drug

idoxuridine, acyclovir, vidarabine, gancyclovir and the like.

(vi) anti-HIV agent

zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate,ritonavir and the like.

(vii) antispirochetele(viii) Antibiotic

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox,cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime,cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin,aztreonam or a salt thereof, griseofulvin, lankacidin-group [Journal ofAntibiotics (J. Antibiotics), 38, 877-885(1985)], azole compound[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone,fluconazole, itraconazole and the like] and the like.

(2) antifungal agent(i) polyethylene antibiotic (e.g., amphotericin B, nystatin,trichomycin)(ii) griseofulvin, pyrrolnitrin and the like(iii) cytosine metabolism antagonist (e.g., flucytosine)(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazolenitrate, bifonazole, croconazole)(v) triazole derivative (e.g., fluconazole, itraconazole)(vi) thiocarbamic acid derivative (e.g., trinaphthol) and the like.(3) antiprotozoal agent

metronidazole, tinidazole, diethylcarbamazine citrate, quininehydrochloride, quinine sulfate and the like.

(4) antitussive and expectorant drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol,isoproterenol, salbutamol, terbutaline oxymetebanol, morphinehydrochloride, dextromethorfan hydrobromide, oxycodone hydrochloride,dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteinehydrochloride, carbocysteine and the like.

(5) sedative

chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(6) anesthetic(6-1) local anesthetic

cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine and the like.

(6-2) general anesthetic(i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide,isoflurane, enflurane),(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol,thiopental sodium, thiamylal sodium, pentobarbital) and the like.(7) antiulcer drug

histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine,cimetidine, ranitidine, famotidine, urogastrone, oxethazaine,proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate,aldioxa, teprenone, vonoprazan, prostaglandin and the like.

(8) antiarrhythmic agent(i) sodium channel blacker (e.g., quinidine, procainamide, disopyramide,ajmaline, lidocaine, mexiletine, phenytoin),(ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol,carteolol, arotinolol hydrochloride),(iii) potassium channel blocker (e.g., amiodarone),(iv) calcium channel blacker (e.g., verapamil, diltiazem) and the like.(9) hypotensive diuretic drug

hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide,trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefruside,azosemide, spironolactone, potassium canrenoate, triamterene, amiloride,acetazolamide, D-mannitol, isosorbide, aminophylline and the like.

(10) anticoagulant

heparin sodium, sodium citrate, activated protein C, tissue factorpathway inhibitor, antithrombin III, dalteparin sodium, warfarinpotassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethylicosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride,pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase andthe like.

(11) tranquilizer

diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzineand the like.

(12) antipsychotic

chlorpromazine hydrochloride, prochlorperazine, trifluoperazine,thioridazine hydrochloride, perphenazine maleate, fluphenazineenanthate, prochlorperazine maleate, levomepromazine maleate,promethazine hydrochloride, haloperidol, bromperidol, spiperone,reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) antitumor drug

6-O—(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelinacetate and the like.

(14) hypolipidemic drug

clofibrate, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chemical andPharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol,cholestyramine, dextran sulfate sodium and the like.

(15) muscle relaxant

pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine and the like.

(16) antiepileptic drug

phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate,clonazepam, diazepam, nitrazepam and the like.

(17) antidepressant

imipramine, clomipramine, noxiptiline, phenelzine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride and the like.

(18) antiallergic drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azelastine hydrochloride, epinastine, ozagrelhydrochloride, pranlukast hydrate, seratrodast and the like.

(19) cardiac stimulants

trans-π-oxocamphor, terephyllol, aminophylline, etilefrine, dopamine,dobutamine, denopamine, aminophylline, vesnarinone, amrinone,pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatosideC, G-strophanthin and the like.

(20) vasodilator

oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz and the like.

(21) vasoconstrictor dopamine, dobutamine denopamine and the like.(22) hypotensive diuretic

hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine,diltiazem, nifedipine and the like.

(23) therapeutic drug for diabetes

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide,acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide,phenformin, buformin, metformin, DPP4 inhibitor, insulin preparation andthe like.

(24) antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(25) liposoluble vitamins(i) vitamin A: vitamin A₁, vitamin A₂ and retinol palmitate(ii) vitamin D: vitamin D₁, D₂, D₃, D₄ and D₅(iii) vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol,dl-α-tocopherol nicotinate(iv) vitamin K: vitamin K₁, K₂, K₃ and K₄(v) folic acid (vitamin M) and the like.(26) vitamin derivative

various derivatives of vitamins, for example, vitamin D₃ derivativessuch as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol, calcipotriol and the like, vitamin D₂derivatives such as 5,6-trans-ergocalciferol and the like, and the like.

(27) antiasthmatic

isoprenaline hydrochloride, salbutamol sulfate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophylline, aminophylline, sodiumcromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen,terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,pranlkast hydrate, seratrodast, dexamethasone, prednisolone,hydrocortisone, hydrocortisone sodium succinate, beclometasonedipropionate, ciclesonide and the like.

(28) therapeutic agent for pollakisuria/anischuria

flavoxate hydrochloride and the like.

(29) therapeutic agent for atopic dermatitis

sodium cromoglicate and the like.

(30) therapeutic agent for allergic rhinitis

sodium cromoglicate, chlorpheniramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine,mequitazine, ketotifen fumarate, cetirizine hydrochloride, oxatomide,azelastine, ebastine, epinastine hydrochloride, loratadine and the like.

(31) hypertensor

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin and the like.

(32) therapeutic agent for dry eye

artificial tears, therapeutic agent for corneal and conjunctiveepithelium disorder, diquafosol sodium and the like.

(32) others

hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins,lamivudine, adefovir, entecavir, tenofovir, peginterferon α, ribavirin,telaprevir, simeprevir, vaniprevir, daclatasvir, asunaprevir,sofosbuvir, glycyrrhetinic acid, ursodeoxycholic acid and the like.

For combined use, the administration time of the compound of the presentinvention and the concomitant drug is not restricted, and the compoundof the present invention or the concomitant drug can be administered toan administration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration form of the combined use is not particularly limited,and the compound of the present invention and a concomitant drug onlyneed to be combined on administration. Examples of such administrationmode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the concomitantdrug, (2) simultaneous administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route, (3)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by the same administration route in a staggered manner, (4)simultaneous administration of two kinds of preparations of the compoundof the present invention and the concomitant drug, which have beenseparately produced, by different administration routes, (5)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the concomitant drug, or in the reverse order) and thelike.

The mixing ratio of the compound of the present invention and aconcomitant drug in the combination agent of the present invention canbe appropriately selected based on the subject of administration,administration route, disease and the like.

For example, while the content of the compound of the present inventionin the combination agent of the present invention varies depending onthe preparation form, it is generally about 0.01-100 wt %, preferablyabout 0.1-50 wt %, more preferably about 0.5-20 wt %, of the wholepreparation.

The content of the concomitant drug in the combination agent of thepresent invention varies depending on the preparation form, andgenerally about 0.01 to 100% by weight, preferably about 0.1 to 50% byweight, further preferably about 0.5 to 20% by weight, of the entirepreparation.

While the content of the additive such as a carrier and the like in thecombination agent of the present invention varies depending on the formof a preparation, it is generally about 1 to 99.99% by weight,preferably about 10 to 90% by weight, based on the preparation.

When the compound of the present invention and the concomitant drug areseparately prepared, the same content may be adopted.

The dose varies depending on the kind of the compound of the presentinvention, administration route, symptom, age of patients and the like.For example, for oral administration to patients (body weight about 60kg) with inflammatory bowel disease (IBD), about 0.1 mg/kg bodyweight-about 30 mg/kg body weight, preferably about 1 mg/kg bodyweight-20 mg/kg body weight, of compound (I) can be administered once toseveral portions per day.

The dose of the medicament of the present invention as asustained-release preparation varies depending on the kind and contentof compound (I), dosage form, period of sustained drug release, subjectanimal of administration (e.g., mammals such as mouse, rat, hamster,guinea pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, humanand the like), and administration object. For example, for applicationby parenteral administration, about 0.1 to about 100 mg of compound (I)needs to be released from the administered preparation per 1 week.

Any amount of the concomitant drug can be adopted as long as the sideeffects do not cause a problem. The daily dosage in terms of theconcomitant drug varies depending on the severity, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacology, kind of the pharmaceuticalpreparation, kind of effective ingredient, and the like, and notparticularly restricted, and the amount of a drug is, in the case oforal administration for example, generally about 0.001 to 2000 mg,preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg,per 1 kg of a mammal and this is generally administered once to 4-timesdivided in a day.

When the combination agent of the present invention is administered, thecompound of the present invention and the concomitant drug can beadministered simultaneously, or may be administered in a staggeredmanner. When administered at a time interval, the interval variesdepending on the effective ingredient, dosage form and administrationmethod, and, for example, when the concomitant drug is administeredfirst, a method in which the compound of the present invention isadministered within time range of from 1 minute to 3 days, preferablyfrom 10 minutes to 1 day, more preferably from 15 minutes to 1 hour,after administration of the concomitant drug is an example. When thecompound of the present invention is administered first, a method inwhich the concomitant drug is administered within time range of from 1minute to 1 day, preferably from 10 minutes to 6 hours, more preferablyfrom 15 minutes to 1 hour after administration of the compound of thepresent invention is an example.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, Formulation Examples and Experimental Examples,which are not to be construed as limitative and may be modified withoutdeparting from the scope of the invention.

Unless particularly specified, the elution in column chromatography inthe Examples was performed under observation by TLC (Thin LayerChromatography). For TLC observation, 60F254 manufactured by Merck wasused as a TLC plate, and the solvent used as an elution solvent forcolumn chromatography was used as a developing solvent. For detection, aUV detector was adopted. In silica gel column chromatography, NH meansuse of aminopropylsilane-bonded silica gel, and Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparativeHPLC (high performance liquid chromatography), C18 means use ofoctadecyl-bonded silica gel. The ratios of elution solvents are volumemixing ratios, unless otherwise specified. The room temperaturegenerally means a temperature about 10° C. to 35° C. For dryingextracts, sodium sulfate or magnesium sulfate was used.

The peak by powder X-RAY diffraction in Example means the peak measuredusing Cu Kα-ray as a source by Ultima IV (Rigaku Corporation, Japan) atroom temperature. The measurement conditions are as follows.

Electric pressure/Electric current: 40 kV/50 mA

Scan speed: 6 degree/min

Scan range of 2 Theta: 2-35 degree

The crystallinity by powder X-RAY diffraction in Example was calculatedby Hermans method.

In the chemical structure formulas described in Examples, the wavy linebonded to the asymmetric carbon

means one stereochemical structure which is not determined, and thesolid line

means a mixture of two stereochemical structure.

The abbreviations in the present specification or the Examples mean asfollows.

LC: liquid chromatographyMS: mass analysis spectrumAPI: atmospheric pressure ionization methodM: molecular weight of the compoundNMR: nuclear magnetic resonance spectrumHz: hertzJ: coupling constantm: multipletq: quartett: tripletd: doubletdd: double doubletddd: double double doublets: singletdt: double tripletsxt: sextetbrs: broad singletquin: quintetquant.: quantitativeADDP: 1,1′-(azodicarbonyl)dipiperidineAIBN: 2,2′-azobis(isobutyronitrile)BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBoc: tert-butyloxycarbonyl groupBoc₂O: di-tert-butyl dicarbonateCDI: carbonyldiimidazoleCOMU:1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphateCPME: cyclopentyl methyl etherDBU: 1,8-diazabicyclo[5.4.0]undec-7-eneDEAD: diethyl azodicarboxylate/40% toluene solutionDIAD: diisopropyl azodicarboxylateDIBAL-H: diisobutylaluminium hydrideDIEA: diisopropylethylamineDMA: dimethylacetamideDMAP: 4-dimethylaminopyridineDME: dimethoxyethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxideDPPA: diphenylphosphoryl azideEt₂O: diethyl etherEtCH: ethanolHATU: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphorateHMDS: 1,1,1,2,2,2-hexamethyldisilaneHOBt: 1H-benzo[d][1,2,3]triazol-1-ol hydrateIPE: diisopropyl etherMeCH: methanolM: mol concentrationMEK: methyl ethyl ketoneN: normal concentrationNaHMDS: sodium bis(trimethylsilyl)amide

NBS: N-bromosuccinimide

n-BuLi: 1.6M n-butyllithium/hexane solutionNMP: N-methyl-2-pyrrolidonePd(PPh₃)₄: tetrakis(triphenylphosphine)palladium(0)Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)PdCl₂(dppf):1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethanecomplexPPA: polyphosphoric acidPPh₃: triphenyiphosphinet-: tert-T3P: 1.6M2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide/ethylacetate solution or DMF solutionTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranTMSCl: trimethylsilyl chloride, trimethylsilane chlorideWSC: N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamineWSC.HCl: N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochlorideXANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneLAH: lithium aluminium hydride

Example 1trans-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclopropanecarboxylicacid (a Mixture of Two Diastereomers) (Step 1)

To a solution of 1,3-difluoro-5-nitrobenzene (3 g, 18.86 mmol) in THF(60 mL) was added trimethylsilyl chloride (7.23 mL, 56.57 mmol) at −78°C. under nitrogen atmosphere. To the reaction solution was added sodiumhexamethyldisilazide (19.85 mL, 37.71 mmol), and the mixture was kept at−75° C. or lower. The reaction solution was stirred for 1 hr, and waterand ethyl acetate were added thereto. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; hexane) to give(2,6-difluoro-4-nitrophenyl)trimethylsilane (3.51 g, 15.18 mmol, 80%) asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.42 (9H, s), 7.61-7.71 (2H, m).

A mixture of (2,6-difluoro-4-nitrophenyl)trimethylsilane (3.5 g, 15.13mmol) and 10% palladium-carbon (350 mg, 0.16 mmol, 50% wet) in MeOH (70mL) was stirred at room temperature for 5 hr under hydrogen atmosphere(1 atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent; ethyl acetate/hexane) togive 3,5-difluoro-4-(trimethylsilyl)aniline (2.50 g, 12.42 mmol, 82%) asa pale-yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.30 (9H, s), 3.88 (2H, brs), 5.99-6.16 (2H,m).

(Step 2)

A solution of 3-(2-aminoethyl)phenol hydrochloride (4.60 g, 26.49 mmol)and 47% ethyl glyoxylate/toluene solution (polymer form) (6.15 mL, 29.14mmol) in a mixed solvent of toluene/EtOH (50 mL) was heated under refluxfor 18 hr. The reaction mixture was concentrated under reduced pressure.The precipitate was collected by filtration, and washed with ethylacetate/diethyl ether to give ethyl6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride(6.15 g, 23.86 mmol, 90%) as a white powder.

¹H NMR (300 MHz, DMSO-d₆): δ1.25 (3H, t, J=7.0 Hz), 2.94 (2H, t, J=6.2Hz), 3.35 (1H, brs), 3.38-3.52 (2H, m), 4.26 (2H, q, J=7.1 Hz), 5.27(1H, s), 6.64 (1H, d, J=2.3 Hz), 6.73 (1H, dd, J=8.7, 2.6 Hz), 7.21 (1H,d, J=8.7 Hz), 9.77 (1H, s), 9.99 (1H, br s)

(Step 3)

Boc₂O (5.47 g, 25.06 mmol) was added to a solution of ethyl6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride(6.15 g, 23.86 mmol) and TEA (3.33 mL, 23.86 mmol) in a mixed solvent ofTHF (65 mL) and water (25 mL) at room temperature, and the mixture wasvigorously stirred for 2 hr. The reaction mixture was poured into water(250 mL), and the mixture was extracted with ethyl acetate (×3). Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→30% ethyl acetate/hexane) to give 1-ethyl2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.85 g, 24.43 mmol, quant.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.19-1.29 (3H, m), 1.45-1.52 (9H, m),2.72-2.96 (2H, m), 3.65-3.83 (2H, m), 4.08-4.19 (2H, m), 5.16-5.50 (2H,m), 6.63 (1H, s), 6.67-6.73 (1H, m), 7.31-7.37 (1H, m).

(Step 4)

Iodomethane (3.04 mL, 48.85 mmol) was added to a solution of 1-ethyl2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.85 g, 24.43 mmol) and cesium carbonate (10.35 g, 31.75 mmol) in DMF(50 mL) at room temperature, and the mixture was stirred for 2.5 hr. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate (×3). The organic layer was washed with 0.1% aqueoussodium thiosulfate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give 1-ethyl2-tert-butyl 6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(8.23 g, 24.54 mmol, 100%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.20-1.29 (3H, m), 1.46-1.51 (9H, m),2.75-2.99 (2H, m), 3.69-3.81 (5H, m), 4.08-4.19 (2H, m), 5.33-5.51 (1H,m), 6.68 (1H, s), 6.77 (1H, dd, J=8.3, 2.6 Hz), 7.36-7.43 (1H, m).

(Step 5)

2N Aqueous lithium hydroxide solution (73.6 mL, 147.23 mmol) was addedto a solution of 1-ethyl 2-tert-butyl6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54mmol) in a mixed solvent of EtOH (35 mL) and THF (35 mL) at roomtemperature, and the mixture was stirred for 2 hr. To the reactionmixture was added water, the pH of the mixture was adjusted to 3 with 2Nhydrochloric acid, and the mixture was extracted with ethyl acetate(×3). The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (7.59 g, 24.70 mmol, quant.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.41-1.52 (9H, m), 2.72-3.00 (2H, m),3.56-3.67 (1H, m), 3.71-3.87 (4H, m), 5.33-5.53 (1H, m), 6.68 (1H, d,J=2.3 Hz), 6.77 (1H, dd, J=8.7, 2.3 Hz), 7.37 (1H, d, J=8.7 Hz) (Theexchangeable 1H was not observed).

(Step 6)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (700 mg, 3.48mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1176 mg, 3.83 mmol), DMAP (467 mg, 3.83 mmol) and DIEA (3.04 mg,17.39 mmol) in ethyl acetate (6.0 mL) was added T3P (6.14 mL, 10.43mmol) at room temperature, and the mixture was stirred at 80° C. for 2hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The precipitate was washed with diethyl ether/hexaneto give tert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(994.1 mg, 2.026 mmol, 58.3%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ0.32 (9H, s), 1.52 (9H, s), 2.76-2.98 (2H, m),3.51-3.75 (2H, m), 3.80 (3H, s), 5.58 (1H, brs), 6.73 (1H, d, J=2.3 Hz),6.81 (1H, dd, J=8.3, 2.3 Hz), 6.97-7.07 (2H, m), 7.19 (1H, brs), 9.11(1H, brs).

(Step 7)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(900 mg) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(410 mg, >99.6% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD(NF001) 50 mmID×500 mmL

solvent: hexane/EtOH-850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 8)

Cooled TFA (4.5 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(439 mg, 0.89 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The reaction mixture was poured into ice andaqueous sodium hydrogencarbonate solution, the pH of mixture wasadjusted to 8 with potassium carbonate, and the mixture was extractedwith ethyl acetate (×3). The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The precipitate was washed with IPE/hexane to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(246 mg, 0.630 mmol, 70.4%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=1.1 Hz), 2.23 (1H, brs),2.69-2.80 (1H,m), 2.84-2.94 (1H, m), 3.14 (2H, t, J=5.9 Hz), 3.78 (3H,s), 4.63 (1H, s), 6.64 (1H,d, J=2.6 Hz), 6.78 (1H, dd, J=8.7, 2.6 Hz),7.17 (1H, dd), 7.24-7.30 (1H, m), 7.45 (1H, dd, J=10.6, 1.9 Hz), 7.53(1H, d, J=8.7 Hz), 9.45 (1H, s).

(Step 9)

HATU (161 mg, 0.42 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(150 mg, 0.38 mmol), trans-cyclopropane-1,2-dicarboxylic acid (100 mg,0.77 mmol) and DIEA (0.134 mL, 0.77 mmol) in DMF (2 mL), and the mixturewas stirred at room temperature for 2 hr. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 30→100% ethyl acetate/hexane) to give the title compound.

¹H NMR (300 MHz, DMSO-d₆): δ0.21-0.39 (9H, m), 1.11-1.41 (2H, m),1.64-1.87 (1H,m), 1.90-2.07 (1H, m), 2.88 (1H, d, J=16.2 Hz), 3.10-3.26(1H, m), 3.58-3.83 (4H, m), 4.10-4.35 (1H, m), 5.50-5.69 (1H, m),6.72-6.91 (2H, m), 7.02-7.28 (2H, m), 7.33-7.56 (1H, m), 10.76 (1H, s),12.57 (1H, brs).

Example 2trans-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclopropanecarboxylicacid (Single Stereoisomer, Shorter Retention Time) Example 3trans-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclopropanecarboxylicacid (Single Stereoisomer, Longer Retention Time)

HATU (193 mg, 0.51 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(180 mg, 0.46 mmol), trans-cyclopropane-1,2-dicarboxylic acid (90 mg,0.69 mmol) and DIEA (0.161 mL, 0.92 mmol) in DMF (2 mL), and the mixturewas stirred at room temperature for 2 hr. To the reaction mixture wasadded water to give blue-white precipitates. The precipitate waspurified by silica gel column chromatography (solvent gradient; 40→4100%ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)). The fraction having a shorterretention time was concentrated to give the compound of Example 2 (36mg, 0.072 mmol, 16%), and the fraction having a longer retention timewas concentrated to give the compound of Example 3 (20 mg, 0.040 mmol,9%), respectively.

NMR spectrum of the compound of Example 2

¹H NMR (300 MHz, DMSO-d₆): δ0.22-0.36 (9H, m), 1.21-1.39 (2H, m),1.72-1.88 (1H, m), 2.43-2.51 (1H, m), 2.80-2.96 (1H, m, J=15.9 Hz),3.08-3.25 (1H, m), 3.63-3.82 (4H, m), 4.10-4.30 (1H, m), 5.58 (1H, s),6.77-6.91 (2H, m), 7.10-7.25 (2H, m), 7.47 (1H, d, J=8.3 Hz), 10.76 (1H,s), 12.58 (1H, brs).

NMR spectrum of the compound of Example 3

¹H NMR (300 MHz, DMSO-d₆): δ0.23-0.38 (9H, m), 1.21-1.39 (2H, m),1.75-1.86 (1H, m), 2.80-2.94 (1H, m, J=15.5 Hz), 2.86-2.87 (1H, m), 3.19(1H, ddd, J=15.3, 9.6, 5.3 Hz), 3.59-3.80 (4H, m), 4.10-4.33 (1H, m),5.47-5.96 (1H, m), 6.76-6.90 (2H, m), 7.09-7.27 (2H, m), 7.40-7.57 (1H,m), 10.63-10.96 (1H, m), 12.58 (1H, brs). specific optical rotation ofthe compound of Example 3 [α]_(D) ²⁵ +68.4 (c 0.2000, MeOH)

Example 4(3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

A mixture of 3-oxocyclobutanecarboxylic acid (0.303 g, 2.66 mmol),tert-butyl triphenylphosphoranylidenacetate (1 g, 2.66 mmol) and toluene(5 mL) was stirred overnight at 90° C. The reaction solution wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 70→100%ethyl acetate/hexane) to give3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (0.500 g,2.356 mmol, 89%) as pale-yellow crystals.

¹H NMR (300 MHz, CDCl₃): δ1.47 (9H, s), 2.99-3.55 (5H, m), 5.58 (1H,quin, J=2.3 Hz) (The peak derived from CO₂H was not observed).

(Step 2)

HATU (148 mg, 0.39 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(138 mg, 0.35 mmol), DIEA (0.068 mL, 0.39 mmol) and3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (83 mg,0.39 mmol) in DMF (4 mL), and the mixture was stirred at roomtemperature for 2.5 hr. To the reaction mixture was added water to givepale-yellow precipitates. The precipitate was collected by filtration togive tert-butyl2-(3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutylidene)acetate(138 mg, 0.236 mmol, 67%).

MS(API): Calculated 584.7, Found 583.4 (M-H).

(Step 3)

A mixture of tert-butyl2-(3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutylidene)acetate(138 mg, 0.24 mmol) and 10% palladium-carbon (25.1 mg, 0.24 mmol, 50%,wet) in MeOH (20 mL) was stirred overnight at room temperature underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→50% ethyl acetate/hexane) to give tert-butyl(R)-2-(3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(118 mg, 0.201 mmol, 85%) as a colorless oil.

MS(API): Calculated 586.7, Found 585.4 (M-H).

(Step 4)

Cooled TEA (4 mL) was added to tert-butyl(R)-2-(3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(118 mg, 0.20 mmol) at 0° C., and the mixture was stirred at 0° C. for 1hr. The reaction mixture was poured into ice and aqueous sodiumhydrogencarbonate solution (pH 6), and the mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;10→100% ethyl acetate/hexane) to give the title compound (70.0 mg, 0.132mmol, 65.6%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.71-1.96 (2H, m), 2.21-2.42(4H, m), 2.42-2.62 (1H, m), 2.77 (1H, dt, J=15.4,5.0 Hz), 2.95-3.14(1H,m), 3.15-3.56 (2H, m), 3.72 (3H, s), 3.83-4.06 (1H, m), 5.44-5.70(1H, m), 6.70-6.94 (2H, m), 7.05-7.35 (2H, m), 7.38-7.56 (1H, m),10.66-10.95 (1H, m), 12.06 (1H, brs).

Example 5cis-3-(1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutanecarboxylicacid

HATU (82 mg, 0.22 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) andcis-cyclobutane-1,3-dicarboxylic acid (78 mg, 0.54 mmol) in DMF (2.0 mL)at room temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 20→490% ethyl acetate/hexane),and then preparative HPLC (C18, mobile phase: water/acetonitrile(containing 0.1% TFA)) to give the title compound (29.7 mg, 0.057 mmol,32.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.17-2.44 (4H, m), 2.68-2.87(1H, m), 2.88-3.17 (2H, m), 3.36-3.53 (2H, m), 3.72 (3H, s), 3.82-4.02(1H, m), 5.58 (1H, s), 6.72-6.91 (2H, m), 7.20 (2H, m, J=9.8 Hz),7.37-7.51 (1H, m), 10.81 (1H, s), 11.85-12.49 (1H, m)

Example 6((1R,2S)-2-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)aceticacid (Step 1)

To a solution of 1-bromo-3-fluoro-5-methoxybenzene (15 g, 73.16 mmol),tris(2-methylphenyl)phosphane (1.781 g, 5.85 mmol) and ethyl acrylate(11.90 mL, 109.74 mmol) in TEA (0.135 mL) was added palladium(II)acetate (0.329 g, 1.46 mmol) at room temperature under nitrogenatmosphere, and the mixture was stirred at 90° C. for 2 days. Thesolvent was evaporated under reduced pressure, the residue was dilutedwith water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g, 63.3 mmol,87%) as a colorless oil.

(Step 2)

A mixture of ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g,63.33 mmol) and 10% palladium-carbon (1.4 g, 0.66 mmol, 50%, wet) inEtOH (300 mL) was stirred at room temperature for 5 hr under hydrogenatmosphere (1 atm). The catalyst was removed by filtration throughCelite, and the filtrate was concentrated under reduced pressure to giveethyl 3-(3-fluoro-5-methoxyphenyl)propanoate (13.9 g, 61.4 mmol, 97%) asa colorless oil.

(Step 3)

To a solution of ethyl 3-(3-fluoro-5-methoxyphenyl)propanoate (13.9 g,61.44 mmol) in anhydrous THF (200 mL) was added dropwise 3Mmethylmagnesium bromide/diethyl ether solution (61.4 mL, 164.31 mmol) at0° C., and the mixture was stirred at room temperature for 1 hr undernitrogen atmosphere. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure to give 4-(3-fluoro-5-methoxyphenyl)-2-methylbutan-2-ol(12.1 g, 57.01 mmol, 93%). This compound was used for the next stepwithout purification.

(Step 4)

A mixture of 4-(3-fluoro-5-methoxyphenyl)-2-methylbutan-2-ol (12.1 g,57.01 mmol) and PPA (100 g, 57.01 mmol) was stirred at 90° C. for 1 hr.The reaction mixture was poured into ice water, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give7-fluoro-5-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene (4.76 g, 24.51mmol, 43%) as a colorless oil.

(Step 5)

To a solution of 7-fluoro-5-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene(4.76 g, 24.51 mmol) and 1-dodecanethiol (17.71 mL, 73.52 mmol) intoluene (50 mL) was added aluminium chloride (9.80 g, 73.52 mmol) at 0°C., and the mixture was stirred at room temperature for 2 hr. To thereaction mixture was added 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (4.17 g, 23.14 mmol,94%) as an off-white solid.

(Step 6)

To a solution of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (4.17g, 23.14 mmol) in THF (80 mL) was added sodium hydride (60%, oil, 1.111g, 27.77 mmol) at 0° C., and the mixture was stirred at room temperature15 min. Then,1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(9.09 g, 25.45 mmol) was added thereto at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was pouredinto ice water, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate (6.21 g, 19.89 mmol, 86%) as a colorless oil.

(Step 7)

A mixture of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate (5.18 g, 16.59 mmol), diphenylmethanimine(3.61 g, 19.91 mmol), Pd₂(dba)₃ (0.759 g, 0.83 mmol), BINAP (1.033 g,1.66 mmol), sodium tert-butoxide (2.391 g, 24.88 mmol) and toluene (75mL) was stirred at 80° C. for 2 hr. The reaction mixture was poured intowater, and the mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was dissolved in THF (200mL), 1N hydrochloric acid (83 mL, 82.94 mmol) was added thereto, and themixture was stirred at room temperature for 30 min, and basified with 1Naqueous sodium hydroxide solution. The mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (1.92 g, 10.71 mmol,65%) as an orange oil.

¹H NMR (300 MHz, CDCl₃): δ1.34 (6H, s), 1.89 (2H, t, J=7.4 Hz), 2.82(2H,t,J=7.2 Hz), 3.61 (2H, brs), 6.13-6.21 (1H, m), 6.28-6.33 (1H, m).

(Step 8)

Morpholine (261 mg, 261 μL, 2.99 mmol) and acetic acid (200 mg, 191 μL,3.32 mmol) were added to a solution of2,2-dimethyl-1,3-dioxane-4,6-dione (24.0 g, 166.17 mmol) in acetone (120g) at room temperature under argon atmosphere, and the mixture wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure. To the obtained residue was addedsaturated aqueous sodium hydrogencarbonate solution (200 mL), and themixture was extracted with toluene (200 mL). The organic layer waswashed with 10% brine (200 mL), and the solvent was evaporated underreduced pressure to give5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid.The obtained white solid was subjected to azeotropy with toluene (100mL) (×2).

¹H NMR (500 MHz, CDCl₃): δ1.72 (6H, s), 2.52 (6H, s).

A solution (183 mL, 182.79 mmol) of 1M isopropylmagnesium chloride inTHF was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene(50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C.under argon atmosphere. The reaction mixture was stirred at −20° C. for30 min, and added dropwise to a solution of5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene(84 mL) over 20 min at −20° C., and then the used container was washedwith THF (24 mL). The reaction mixture was stirred at 0° C. for 3 hr,10% aqueous citric acid solution (200 mL) was added thereto at 0° C.,and the mixture was extracted with toluene (200 mL). The organic layerwas concentrated under reduced pressure to give5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a pale-yellow oil.

4M Hydrochloric acid (96 mL) was added to a solution of5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dionein DMF (60 mL), and the mixture was stirred at 100° C. for 24 hr. Thereaction mixture was concentrated under reduced pressure at 75° C., andthe pH of the obtained residue were adjusted to 9.0 with DMF (40 mL),water (100 mL), 8M aqueous sodium hydroxide solution (50 mL), 6Mhydrochloric acid (about 10 mL) and 8M aqueous sodium hydroxide solution(10 mL). The mixture was stirred at 0° C. for 10 min, and filtered, andthe filtrate was washed with water (100 mL). The pH of the filtrate wasadjusted to 4.0 with 6M hydrochloric acid (20 mL) at 0° C., and mixturewas stirred at 0° C. for 1 hr. The precipitate was collected byfiltration, washed with ice water, and dried at 50° C. to give3-(4-bromo-2-fluorophenyl)-3-methylbutanoic acid (23.52 g, 85.49 mmol,51%) as white crystals.

¹H NMR (500 MHz, CDCl₃): δ1.46 (6H, s), 2.80 (2H, s), 7.13-7.22 (3H, m)

(The peak derived from COOH was not observed).

(Step 9)

A mixture of 3-(4-bromo-2-fluorophenyl)-3-methylbutanoic acid (20.0 g,72.70 mmol) and PPA (200 g) was stirred at 100° C. for 4 hr. To thereaction mixture was added ice water (200 mL) at 0° C., and the mixturewas extracted with ethyl acetate (200 mL) (×2). To the organic layer wasadded saturated aqueous sodium hydrogencarbonate solution (200 mL), andthe pH of the aqueous layer was adjusted to 7.0 with 8M aqueous sodiumhydroxide solution (35 mL). The organic layer was washed with 10% brine(200 mL), and concentrated under reduced pressure. The obtained residuewas subjected to azeotropy with ethanol (600 mL). To a mixture of theobtained residue in DMF (140 mL) and EtOH (140 mL) was added water (240mL) at room temperature, and the mixture was stirred at 0° C. for 2 hr.The precipitate was collected by filtration, washed with water (100 mL),and dried at 50° C. to give 6-bromo-4-fluoro-3,3-dimethylindan-1-one(17.0 g, 66.12 mmol, 91%) as pale-orange crystals.

¹H NMR (500 MHz, CDCl₃): δ1.52 (6H, s), 2.63 (2H, s), 7.41(1H,dd,J=9.0,1.7 Hz), 7.65 (1H, d, J=1.6 Hz).

(Step 10)

Triethylsilane (1.59 g, 2.17 mL, 13.63 mmol) was added to a solution of6-bromo-4-fluoro-3,3-dimethylindan-1-one (1.5 g, 5.83 mmol) in TFA (30mL) at room temperature, and the mixture was stirred at room temperaturefor 40 hr. To the reaction mixture was added ice water at 0° C., and themixture was extracted with ethyl acetate (×2). The organic layer waswashed with aqueous sodium hydroxide solution (the pH of the aqueouslayer was adjusted to 7.0) and 10% brine, dried over sodium sulfate, andconcentrated under reduced pressure to give crude5-bromo-7-fluoro-1,1-dimethylindane as an orange oil.

¹H NMR (500 MHz, CDCl₃): δ1.35 (6H, s), 1.93 (2H, t, J=7.3 Hz), 2.90(2H,t,J=7.4 Hz), 6.98 (1H,dt,J=9.5,0.8 Hz), 7.06-7.13 (1H, m).

Pd₂(dba)₃ (267 mg, 0.29 mmol), BINAP (363 mg, 0.58 mmol), sodiumtert-butoxide (841 mg, 8.75 mmol) and benzophenone imine (1.05 g, 0.98mL, 5.83 mmol) were added to a solution of the crude5-bromo-7-fluoro-1,1-dimethylindane in anhydrous toluene (30 mL) at roomtemperature, and the mixture was stirred at 80° C. for 1 hr under argonatmosphere. To the reaction mixture was added ice water, and the mixturewas extracted with ethyl acetate (×2). The organic layer wasconcentrated under reduced pressure to give crudeN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,1-diphenylmethanimineas an orange oil.

To a solution of the crudeN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,1-diphenylmethaniminein THF (30 mL) was added 1M hydrochloric acid (29 mL, 29.17 mmol) atroom temperature, and the mixture was stirred at room temperature for 30min. The pH of the reaction mixture was adjusted to >7 with sodiumhydroxide, and the mixture was extracted with ethyl acetate (×2). Theorganic layer was washed with 10% brine, dried over sodium sulfate, andconcentrated under reduced pressure to give the crude7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine as an orange oil.

¹H NMR (500 MHz, CDCl₃): δ1.32 (6H, s), 1.88 (2H, t, J=7.4 Hz), 2.81(2H,t,J=7.4 Hz), 3.59 (2H, s), 6.15-6.17 (1H, m), 6.28-6.29 (1H, m).

A solution of (+)-camphorsulfonic acid (1.49 g, 6.42 mmol) in ethylacetate (37.5 mL) was added to a solution of the crude7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine in ethyl acetate (15mL) at room temperature, and the used container was washed with ethylacetate (7.5 mL). The mixture was stirred at 0° C. for 1 hr, andfiltered, and the used filter was washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure, ethyl acetate (60 mL)was added to the residue, and the mixture was stirred at 0° C. for 2 hr.The precipitate was collected by filtration, washed with ethyl acetate,and dried over at 40° C. to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (+)-camphorsulfonate(1.38 g, 3.36 mmol, 58%) as pale-yellow crystals.

¹H NMR (500 MHz, CDCl₃): δ0.74 (3H, s), 0.93 (3H, s), 1.22-1.30 (1H, m),1.34 (6H, s), 1.52-1.60 (1H, m), 1.77-1.90 (2H, m), 1.93 (2H, t, J=7.4Hz), 1.96-2.00 (1H, m), 2.23-2.30 (1H, m), 2.35-2.44 (1H, m), 2.74 (1H,d, J=14.8 Hz), 2.91 (2H, t, J=7.4 Hz), 3.31 (1H, d, J=14.5 Hz),7.05-7.10 (1H, m), 7.15-7.20 (1H, m), 8.58-10.43 (2H, br) (Theexchangeable 1H was not observed).

(Step 11)

1.6M n-Butyllithium/hexane solution (282 mL, 451.96 mmol) was addeddropwise to a solution of 2-methoxy-6-methylpyridine (50.60 g, 410.87mmol) in THF (625 mL) over 1 hr at −78° C. under argon atmosphere. Thereaction mixture was stirred at −78° C. for 45 min, paraformaldehyde(49.3 g, 1643.49 mmol) was added thereto at −78° C., and the mixture wasstirred vigorously at room temperature for 3.5 hr. The reaction mixturewas poured into ice water (1000 mL), and NaCl was added thereto to givea saturated solution. The saturated solution was extracted with a mixedsolvent of ethyl acetate/THF (3:1) (×3). The organic layer was washedwith water and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 8-50% ethylacetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanol (23.22 g, 152mmol, 37%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ2.94 (2H, t, J=5.5 Hz), 3.91 (3H, s), 4.00(2H,q,J=4.5 Hz), 4.30 (1H,t,J=5.9 Hz), 6.62 (1H, d, J=8.3 Hz), 6.73 (1H,d, J=7.2 Hz), 7.51 (1H,dd,J=8.3, 7.2 Hz).

(Step 12)

ADDP (49.0 g, 194.09 mmol) was added to a mixture of2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide(24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF(340 mL) at 0° C. under argon atmosphere to give a solution. Thesolution was stirred at room temperature for 16 hr, to the reactionmixture was added ethyl acetate (about 500 mL), and the mixture wasstirred at 0° C. for 20 min. The insoluble substance was removed byfiltration with ethyl acetate, and washed with ethyl acetate. Thefiltrate was poured into water (1000 mL), and the mixture was extractedwith ethyl acetate (×3). The organic layer was washed with water andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 5→20% ethyl acetate/hexane),and the precipitate was collected by filtration with hexane to give2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103mmol, 69%) as an off-white powder.

¹H NMR (300 MHz, CDCl₃): δ3.08 (2H,t,J=7.2 Hz), 3.78 (3H, s), 4.11(2H,t,J=7.2 Hz), 6.54 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=7.2 Hz), 7.43(1H,dd,J=8.3,7.2 Hz), 7.70 (2H, dd, J=5.5, 3.2 Hz), 7.82 (2H, dd, J=6.3,3.0 Hz).

(Step 13)

Hydrazine monohydrate (24.94 mL, 514.18 mmol) was added to a solution of2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 102.84mmol) in EtOH (300 mL) at room temperature. The mixture was heated underreflux for 1 hr, and allowed to be cooled to room temperature. Theinsoluble substance was removed by filtration, and washed with a mixedsolvent of diethyl ether/IPE (1:1). The filtrate was concentrated underreduced pressure, and to the obtained residue was added toluene (about250 mL), and the mixture was concentrated again under reduced pressure.The obtained residue was purified by silica gel column chromatography(NH, solvent gradient; 10→100% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 95 mmol, 92%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.31 (2H, brs), 2.82 (2H,t,J=7.5 Hz), 3.11(2H, t, J=6.0 Hz), 3.92 (3H, s), 6.57 (1H, d, J=7.9 Hz), 6.73 (1H, d,J=7.2 Hz), 7.48 (1H,dd,J=8.1,7.4 Hz).

(Step 14)

1.6M n-Butyllithium/hexane solution (300 mL, 479.43 mmol) was added to asolution of acetonitrile (21.87 g, 532.70 mmol) in THF (630 mL) at −78°C. under argon atmosphere, and the mixture was stirred at −78° C. for 30min. 2-Bromo-6-methoxypyridine (25.04 g, 133.18 mmol) was added dropwisethereto over 15 min at −78° C., and the reaction mixture was stirred atroom temperature for 4 hr. The reaction mixture was poured into icewater (900 mL), and the mixture was extracted with ethyl acetate (×3).The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→20% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)acetonitrile (11.37 g, 77 mmol, 58%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ3.81 (2H, s), 3.93 (3H, s), 6.69 (1H, d, J=8.3Hz), 6.93-6.98 (1H, m), 7.58 (1H, dd, J=8.3, 7.6 Hz).

(Step 15)

A solution of 2-(6-methoxypyridin-2-yl)acetonitrile (5.00 g, 33.75 mmol)in 2M ammonia/MeOH (84 mL, 168.73 mmol) was stirred in the presence ofRaney-nickel (8 g, 136.30 mmol) [obtained by washing Kawaken NDHT-90with 4N aqueous sodium hydroxide solution (40 mL), water (×5) and MeOH(×3)] at room temperature for 22 hr under hydrogen atmosphere (0.5 MPa).The catalyst was removed by decantation, and the reaction solution wasconcentrated under reduced pressure. To the obtained residue was addedtoluene (about 80 mL), and the mixture was concentrated again underreduced pressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 10→100% ethyl acetate/hexane) togive 2-(6-methoxypyridin-2-yl)ethanamine (4.30 g, 28.3 mmol, 84%) as ayellow oil.

(Step 16)

A solution of 2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 94.81 mmol),4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethylglyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol) inEtOH (175 mL) was heated under reflux for 8 hr. To the reaction mixturewere added 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47%ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol),and the mixture was heated again under reflux for 16 hr. The reactionmixture was concentrated under reduced pressure to half volume, and tothe residue was added diethyl ether (ca.150 mL). The precipitate wascollected by filtration, and washed with EtOH/diethyl ether to givecrude ethyl 2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (20.01 g, 77 mmol, 82%) as an off-white powder.

¹H NMR (300 MHz, DMSO-d₆): δ1.25 (3H, t, J=7.0 Hz), 2.71-2.93 (2H, m),3.37-3.51 (2H, m), 4.19-4.31 (2H, m), 5.23 (1H, s), 6.30 (1H, d, J=9.4Hz), 7.43 (1H, d, J=9.4 Hz), 8.12 (1H,brs), 9.65 (1H, brs), 10.56 (1H,brs).

(Step 17)

Boc₂O (17.72 g, 81.22 mmol) was added to a mixture of ethyl2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (20.01 g, 77.3.5 mmol), TEA (11.32 mL, 81.22 mmol), THF(205 mL) and water (75 mL) at room temperature, and the mixture wasstirred vigorously at room temperature for 5.5 hr. The reaction mixturewas poured into water (500 mL), and the mixture was saturated with NaCl,and extracted with a mixed solvent of ethyl acetate/THF (3:1) (×3). Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was collected by filtration, and washed with IPE/hexane togive 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (16.57 g,51.4 mmol, 66%) as a white powder.

¹H NMR (300 MHz, CDCl₃): δ1.24-1.32 (3H, m), 1.45-1.50 (9H, m),2.66-2.92 (2H, m), 3.37-3.55 (1H, m), 4.10-4.29 (3H, m), 5.18-5.43 (1H,m), 6.46 (1H, d, J=9.4 Hz), 7.58-7.66 (1H, m), 12.94 (1H, brs).

(Step 18)

Iodomethane (8.69 mL, 139.60 mmol) was added to a mixture of 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (7.50 g,23.27 mmol), silver(I) carbonate (8.34 g, 30.25 mmol) and THF (150 mL)at room temperature (the reaction vessel was protected from light). Themixture was stirred at room temperature for 15 hr, and then at 50° C.for 5 hr. The insoluble substance was removed by filtration throughCelite, and washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (solvent gradient; 5→30% ethyl acetate/hexane)to give 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.93 g,20.60 mmol, 89%) as a pale-yellow oil.

¹H NMR (300 MHz, CDCl₃): δ1.21-1.30 (3H, m), 1.44-1.53 (9H, m),2.84-2.96 (2H, m), 3.55-3.70 (1H, m), 3.91 (3H, s), 4.01-4.22 (3H,m),5.33-5.54 (1H, m), 6.60 (1H, d, J=8.7 Hz), 7.69 (1H, t, J=7.5 Hz).

(Step 19)

Trimethyloxonium tetrafluoroborate (1.775 g, 12.00 mmol) was added to amixture of 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (1.289 g,4.00 mmol) and acetonitrile (18 mL) at 0° C. The mixture was stirred at0° C. for 2 hr, and the reaction mixture was poured into ice-cooledsaturated aqueous sodium hydrogencarbonate solution (100 mL), and themixture was extracted with ethyl acetate (×3). The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 2→19%ethyl acetate/hexane) to give 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (372 mg,1.106 mmol, 28%) as a colorless oil.

(Step 20)

2N Aqueous lithium hydroxide solution (61.8 mL, 123.61 mmol) was addedto a solution of 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.93 g,20.60 mmol) in a mixed solvent of EtOH (30 mL) and THF (30 mL) at roomtemperature, and the mixture was stirred at room temperature for 1.5 hr.The reaction mixture was poured into ice-cooled water, and the pH of themixture was adjusted to 4 with 6N hydrochloric acid. Then, the mixturewas extracted with a mixed solvent of mixed ethyl acetate/THF (3:1)(×3). The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (6.37 g, 20.66 mmol, 100%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.44-1.52 (9H, m), 2.85-2.95 (2H, m),3.57-3.68 (1H, m), 3.90 (3H, s), 3.97-4.07 (1H, m), 5.36-5.57 (1H, m),6.61 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=8.7 Hz) (The exchangeable 1H wasnot observed).

(Step 21)

T3P (4.89 mL, 8.22 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.69 g, 5.48 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.982 g, 5.48 mmol),DIEA (4.77 mL, 27.41 mmol) and DMAP (0.737 g, 6.03 mmol) in ethylacetate (40 mL) at room temperature. The mixture was stirred at 65° C.for 15 hr, the reaction mixture was poured into water (150 mL), and themixture was extracted with ethyl acetate (×3). The organic layer waswashed with 10% aqueous citric acid solution, aqueous sodiumhydrogencarbonate solution, water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained precipitate was washed with hexane to give tert-butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.09 g, 4.45 mmol, 81%) as an off-white powder.

¹H NMR (300 MHz, CDCl₃): δ1.34 (6H, s), 1.53 (9H, s), 1.91 (2H, t, J=7.4Hz), 2.83-3.01 (4H, m), 3.45 (1H, brs), 3.91 (3H, s), 4.06(1H,dt,J=13.2,4.9 Hz), 5.56 (1H,brs), 6.64 (1H, d, J=8.3 Hz), 7.05-7.12(2H, m), 7.48 (1H, brs), 8.70 (1H, brs).

(Step 22)

tert-Butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(960 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(920 mg, >99% ee), as an off-white amorphous solid, respectively.

purification condition by chiral column chromatography

column: CHIRALPAK IA(QK001) 50 mmID×500 mm

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 23)

TFA (13 mL) was added to tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(957 mg, 2.04 mmol) at room temperature, and the mixture was stirred atroom temperature for 20 min. The reaction mixture was poured intoice-cooled saturated aqueous sodium hydrogencarbonate solution (110 mL),and the pH of the mixture was adjusted to 8 with potassium carbonate.Then, the mixture was extracted with ethyl acetate (×3). The organiclayer was washed with water and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(732 mg, 1.981 mmol, 97%) as an off-white amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.34 (6H, s), 1.69 (1H, brs), 1.91 (2H, t,J=7.4 Hz), 2.73-2.98 (4H, m), 3.12-3.28 (2H, m), 3.90 (3H, s), 4.57 (1H,s), 6.60 (1H, d,J=8.7 Hz), 7.11-7.17 (2H, m), 7.84 (1H, d, J=8.7 Hz),9.41 (1H, s).

(Step 24)

To a solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (25.97 g,223.66 mmol) in THF (125 mL) were added p-toluenesulfonyl chloride (44.8g, 234.84 mmol), pyridine (45.2 mL, 559.14 mmol) and DMAP (30.1 g,246.02 mmol) at 0° C., and the mixture was stirred at room temperaturefor 4 hr. The reaction mixture was poured into ice water (400 mL), andthe pH of the mixture was adjusted to 3 with 6N hydrochloric acid. Then,the mixture was extracted with ethyl acetate (×3). The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The crystals werecollected by filtration, and washed with IPE/hexane to give(S)-(5-oxotetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate (51.81g, 192 mmol, 86%) as a white powder.

¹H NMR (300 MHz, CDCl₃): δ2.06-2.20 (1H, m), 2.28-2.42 (1H, m), 2.46(3H, s), 2.49-2.67 (2H, m), 4.10-4.22 (2H, m), 4.64-4.73 (1H, m), 7.37(2H, d, J=7.9 Hz), 7.79 (2H, d, J=8.3 Hz).

(Step 25)

28% Sodium methoxide/MeOH solution (74.0 g, 383.35 mmol) was added to amixture of (S)-(5-oxotetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate (51.81 g, 191.67 mmol) and dehydrated MeOH (280mL) at room temperature, and the mixture was stirred at room temperaturefor 1.5 hr. The reaction mixture was cooled under ice-cooling, and themixture was neutralized with acetic acid (about 15 mL). The reactionmixture was concentrated to about half-volume under reduced pressure,and ice water (350 mL) was added thereto. Then, the mixture wasextracted with a mixed solvent of ethyl acetate/diethyl ether (3:1)(×3). The organic layer was washed successively with aqueous sodiumhydrogencarbonate solution, water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givecrude methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 101 mmol, 53%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.78 (1H,dq,J=14.0,7.1 Hz), 1.99(1H,dtd,J=14.5, 7.4,4.4 Hz), 2.48 (2H, t, J=7.4 Hz), 2.50-2.53 (1H, m),2.77 (1H, dd, J=5.0, 4.0 Hz), 2.95-3.03 (1H, m), 3.69 (3H, s).

(Step 26)

1.6M n-Butyllithium/hexane solution (76 mL, 120.98 mmol) was addeddropwise to a solution of diisopropylamine (12.24 g, 120.98 mmol) in THF(240 mL) at 0° C. over 12 min under argon atmosphere. The mixture wasstirred at 0° C. for 30 min, and the reaction mixture was cooled to −78°C. A solution of methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 100.81mmol) in THF (10 mL) was added dropwise thereto at −78° C. over 12 min.The reaction mixture was stirred at −15° C. for 2 hr, and poured intocooled 0.5N hydrochloric acid (600 mL), and the mixture was extractedwith ethyl acetate (×3). The organic layer was washed with water andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 49→70% ethyl acetate/hexane) togive methyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (2.27 g,17.44 mmol, 17%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.88 (1H, ddd, J=8.5, 6.2, 4.2 Hz), 1.19-1.29(1H, m), 1.49 (1H, t, J=5.7 Hz), 1.55-1.61 (1H, m), 1.74(1H,dqd,J=8.9,6.3,4.2 Hz), 3.48 (1H,ddd,J=11.6, 6.5, 5.7 Hz), 3.63 (1H,dd, J=11.5, 6.0 Hz), 3.68 (3H, s).

(Step 27)

Sodium hydride (60%, oil, 0.907 g, 22.68 mmol) was added to a solutionof methyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (2.27 g,17.44 mmol) in THF (110 mL) at 0° C. under argon atmosphere. Thereaction mixture was stirred at room temperature for 1 hr, and cooled to0° C. To the reaction mixture were added benzyl bromide (2.70 mL, 22.68mmol) and tetra-n-butylammonium iodide (0.644 g, 1.74 mmol), and themixture was stirred at room temperature for 15 hr. The reaction mixturewas poured into cooled 0.5N hydrochloric acid (350 mL), and the mixturewas extracted with ethyl acetate (×3). The organic layer was washed withwater and brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 2→25% ethylacetate/hexane) to give methyl(1S,2S)-2-((benzyloxy)methyl)cyclopropanecarboxylate (1.38 g, 6.27 mmol,36%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.87 (1H, ddd, J=8.4, 6.4, 4.6 Hz), 1.18-1.29(1H, m), 1.55-1.61 (1H, m), 1.75 (1H,dqd,J=8.7,6.3,4.2 Hz), 3.34(1H,dd,J=10.4,6.4H z), 3.46 (1H,dd,J=10.4,6.4 Hz), 3.67 (3H, s), 4.52(2H, s), 7.27-7.38 (5H, m).

(Step 28)

Lithium aluminium hydride (0.238 g, 6.27 mmol) was added to a solutionof methyl (1S,2S)-2-((benzyloxy)methyl)cyclopropanecarboxylate (1.38 g,6.27 mmol) in THF (15 mL) at 0° C. The reaction mixture was stirred atroom temperature for 15 hr, and ethyl acetate (5 mL) and saturatedaqueous potassium sodium tartrate solution (25 mL) were added thereto at0° C. The mixture was stirred at room temperature for 30 min, water (60mL) was added thereto, and the mixture was extracted with ethyl acetate(×3). The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 37→58% ethyl acetate/hexane) to give((1S,2S)-2-((benzyloxy)methyl)cyclopropyl)methanol (1.01 g, 5.25 mmol,84%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.50 (2H, dd, J=7.0, 5.9 Hz), 0.97-1.09 (2H,m), 1.55 (1H, t, J=5.7 Hz), 3.30 (1H, dd, J=10.4, 6.5 Hz), 3.37-3.55(3H, m), 4.53 (2H, s), 7.26-7.36 (5H,m).

(Step 29)

Methanesulfonyl chloride (443 μL, 5.72 mmol) was added to a solution of((1S,2S)-2-((benzyloxy)methyl)cyclopropyl)methanol (1.00 g, 5.20 mmol)and TEA (797 μL, 5.72 mmol) in THF (15 mL) at 0° C., and the mixture wasstirred at room temperature for 3 hr. The reaction mixture was pouredinto water (80 mL), and the mixture was extracted with ethyl acetate(×3). The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was dissolved in DMF (15 mL), andpotassium cyanide (0.677 g, 10.40 mmol) was added thereto at roomtemperature. The reaction mixture was stirred at 60° C. for 2 hr, andpoured into water (100 mL), and the mixture was extracted with ethylacetate (×3). The organic layer was washed with water and brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 17→38% ethyl acetate/hexane) to give2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetonitrile (782 mg, 3.89mmol, 75%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.56-0.67 (2H, m), 0.93-1.05 (1H, m), 1.12(1H,dqd,J=8.3,6.2,4.2 Hz), 2.35 (1H,dd,J=17.5,6.5H z), 2.48 (1H, dd,J=17.5, 6.5 Hz), 3.32 (1H, dd, J=10.5, 6.6 Hz), 3.42 (1H,d d,J=10.5,6.6Hz), 4.52 (2H, s), 7.27-7.38 (5H, m).

(Step 30)

4N Aqueous sodium hydroxide solution (14.48 mL, 57.91 mmol) was added toa solution of 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetonitrile(777 mg, 3.86 mmol) in EtOH (14.5 mL) at room temperature, and themixture was stirred at 80° C. for 15 hr. The reaction mixture was pouredinto ice water (80 mL), and the pH of the mixture was adjusted to 3 with6N hydrochloric acid. Then, the mixture was extracted with ethyl acetate(×3). The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetic acid (890 mg,4.04 mmol, quant.) as a pale-yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.46-0.61 (2H, m), 0.90-1.06 (2H, m), 2.33(2H, d, J=6.8 Hz), 3.33 (1H, dd, J=10.2, 6.8 Hz), 3.40 (1H,dd,J=10.2,6.4Hz), 4.54 (2H, s), 7.27-7.38 (5H, m) (The peak derived from COOH was notobserved).

(Step 31)

A mixture of 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetic acid(884 mg, 4.01 mmol) in MeOH (20 mL) was stirred in the presence of 10%palladium-carbon (310 mg, 50%, wet) at room temperature for 3 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. To the residue wasadded toluene (about 20 mL), and the mixture was concentrated to give2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (542 mg, 4.16 mmol,quant.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.46-0.61 (2H, m), 0.85-1.04 (2H, m), 2.01(1H,dd,J=17.3,9.2 Hz), 2.66 (1H, dd, J=17.4, 4.9 Hz), 3.16 (1H, dd,J=11.0, 8.7 Hz), 3.81 (1H, dd, J=11.0, 5.7 Hz), 5.11 (2H, brs).

(Step 32)

Benzyl bromide (539 μL, 4.53 mmol) was added to a mixture of2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (536 mg, 4.12 mmol),potassium carbonate (626 mg, 4.53 mmol) and DMF (8 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was poured into water (80 mL), and the mixture wasextracted with ethyl acetate (×3). The organic layer was washed withwater and brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 33-453% ethylacetate/hexane) to give benzyl2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (718 mg, 3.26 mmol, 79%)as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.44-0.59 (2H, m), 0.85-1.01 (2H, m),2.00-2.10 (2H, m), 2.63 (1H, dd, J=17.0, 5.3 Hz), 3.17 (1H, ddd, J=11.1,8.1, 3.4 Hz), 3.73 (1H, ddd, J=11.0, 7.5, 5.7 Hz), 5.10-5.19 (2H, m),7.29-7.41 (5H, m).

(Step 33)

Sodium metaperiodate (1729 mg, 8.08 mmol) and ruthenium(IV) oxidehydrate (48.8 mg, 0.32 mmol) were added to a solution of benzyl2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (712 mg, 3.23 mmol) inacetone (11.5 mL) and water (13 mL) at 0° C., and the mixture wasstirred at 0° C. for 2.5 hr. The reaction mixture was poured into water(100 mL), and the mixture was extracted with ethyl acetate (×3). Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give(1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (690 mg,2.95 mmol, 91%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.90 (1H, ddd, J=8.2, 6.3, 4.7 Hz), 1.33(1H,dt,J=9.2,4.6 Hz), 1.51 (1H,dt,J=8.4,4.3 Hz), 1.74-1.86 (1H, m), 2.39(2H, d, J=7.2 Hz), 5.14 (2H, s), 7.29-7.40 (5H, m) (The peak derivedfrom COOH was not observed).

(Step 34)

HATU (1450 mg, 3.81 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(1083 mg, 2.93 mmol),(1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (687 mg,2.93 mmol) and DIEA (1.022 mL, 5.87 mmol) in DMF (14.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was poured into water (120 mL), and the mixture wasextracted with ethyl acetate (×3). The organic layer was washed withwater and brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 37→58% ethylacetate/hexane) to give benzyl2-((1R,2S)-2-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(1.60 g, 2.73 mmol, 93%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ0.87-0.95 (1H, m), 1.27-1.34 (7H, m),1.77-1.93 (4H, m), 2.26 (1H, dd, J=16.1, 8.1 Hz), 2.63 (1H,dd,J=15.9,6.0Hz), 2.84 (2H, t, J=7.4 Hz), 2.95-3.02 (2H, m), 3.71-3.82 (1H, m), 3.93(3H, s), 4.08-4.17 (1H, m), 5.12 (2H, s), 5.95 (1H, s), 6.66 (1H, d,J=8.7 Hz), 6.99 (1H, s), 7.08 (1H, d, J=11.7 Hz), 7.25-7.33 (5H, m),7.41 (1H, d, J=8.3 Hz), 9.17 (1H, s).

(Step 35)

A solution of benzyl2-((1R,2S)-2-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(1.59 g, 2.71 mmol) in MeOH (45 mL) was stirred in the presence of 10%palladium-carbon (550 mg, 50%, wet) at room temperature for 1.5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (Diol, solventgradient; 30→100% ethyl acetate/hexane) to give the title compound (1.24g, 2.502 mmol, 92%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ0.88-0.95 (1H, m), 1.29-1.37 (7H, m),1.77-1.90 (4H, m), 2.16 (1H,dd,J=16.4,8.2 Hz), 2.66 (1H, dd, J=16.1, 5.5Hz), 2.81 (2H, t, J=7.4 Hz), 2.95-3.17 (2H, m), 3.90 (3H, s), 3.92-4.04(1H, m), 4.13-4.23 (1H, m), 5.96 (1H, s), 6.62 (1H, d, J=8.3 Hz), 6.95(1H, s), 7.03 (1H, d, J=12.1 Hz), 7.49 (1H, d, J=8.3 Hz), 9.35 (1H, s)(The peak derived from COOH was not observed).

[α]_(D) ²⁵ +130.6 (c 0.2510, MeOH)

Example 8cis-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutanecarboxylicacid

HATU (226 mg, 0.59 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(200 mg, 0.49 mmol), DIEA (0.169 mL, 0.99 mmol) andcis-cyclobutane-1,3-dicarboxylic acid (214 mg, 1.48 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)) to give the title compound (74.8 mg, 0.141 mmol, 28.5%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.29 (3H, t, J=7.0 Hz),2.19-2.41 (4H, m), 2.70-2.83 (1H, m), 2.84-3.12 (2H, m), 3.26-3.54 (2H,m), 3.86-4.06 (3H,m), 5.58 (1H, s), 6.71-6.86 (2H, m), 7.13-7.27 (2H,m), 7.42 (1H, s), 10.85 (1H, s)

[α]_(D) ²⁵ +14.1 (c 0.2515, MeOH)

Example 9trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutanecarboxylicacid

HATU (226 mg, 0.59 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(200 mg, 0.49 mmol), DIEA (0.169 mL, 0.99 mmol) andtrans-cyclobutane-1,3-dicarboxylic acid (214 mg, 1.48 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→490% ethyl acetate/hexane, 0→4.10%MeOH/ethyl acetate), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(53.8 mg, 0.101 mmol, 20.51%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.29 (9H, s), 1.29 (3H, t, J=7.0 Hz),2.25-2.47 (4H, m), 2.69-2.84 (1H, m), 2.86-3.12 (2H, m), 3.36-3.57 (2H,m), 3.79-3.91 (1H, m), 3.99 (2H,q,J=7.0 Hz), 5.60 (1H, s), 6.74-6.86(2H, m), 7.14-7.27 (2H, m), 7.38-7.49 (1H, m), 10.82 (1H, s), 12.25 (1H,brs)

[α]_(D) ²⁵ +6.7 (c 0.1275, MeOH)

Example 10cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid (Step 1)

Potassium carbonate (575 mg, 4.16 mmol) and benzyl bromide (0.495 mL,4.16 mmol) were added to a solution of cyclobutane-1,3-dicarboxylic acid(cis-trans mixture) (200 mg, 1.39 mmol) in DMF (4.0 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water at room temperature, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→45% ethylacetate/hexane) to give dibenzyl cis-cyclobutane-1,3-dicarboxylate(106.3 mg, 0.328 mmol, 23.6%) as a less polar compound, and dibenzyltrans-cyclobutane-1,3-dicarboxylate (103.1 mg, 0.318 mmol, 22.9%) as amore polar compound, respectively. NMR spectrum of dibenzylcis-cyclobutane-1,3-dicarboxylate

¹H NMR (300 MHz, CDCl₃): δ2.56 (4H, t, J=7.9 Hz), 3.20-3.34 (2H, m),5.15 (4H, s), 7.29-7.44 (10H, m)

NMR spectrum of dibenzyl trans-cyclobutane-1,3-dicarboxylate

¹H NMR (300 MHz, CDCl₃): δ2.40-2.69 (4H, m), 2.99-3.21 (2H, m), 5.12(4H, s), 7.29-7.41 (10H,m)

(Step 2)

To a solution of dibenzyl cis-cyclobutane-1,3-dicarboxylate (5.29 g,16.31 mmol) in MeOH (100 mL) was added 10% palladium-carbon (500 mg,50%, wet), and the mixture was stirred at room temperature for 5 hrunder hydrogen atmosphere (1 atm). The catalyst was removed byfiltration through Celite, and the filtrate was concentrated underreduced pressure. The residue was solidified with hexane to give crudecis-cyclobutane-1,3-dicarboxylic acid (2.23 g, 15.47 mmol, 95%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ2.17-2.38 (4H,m), 2.88-3.06 (2H, m), 12.17(2H, brs)

(Step 3)

HATU (124 mg, 0.32 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.27 mmol), DIEA (0.093 mL, 0.54 mmol) andcis-cyclobutane-1,3-dicarboxylic acid (58.5 mg, 0.41 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 20→90% ethylacetate/hexane), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(44.5 mg, 0.090 mmol, 33%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (6H, s), 1.87 (2H,t,J=7.4 Hz),2.23-2.45 (4H, m), 2.71-2.91 (3H, m), 2.92-3.09 (2H, m), 3.37-3.51 (1H,m), 3.69-3.80 (1H, m), 3.82 (3H, s), 3.89-4.02 (1H, m), 5.70 (1H, s),6.72 (1H, d, J=8.3 Hz), 7.11-7.31 (2H, m), 7.78 (1H, d, J=8.7 Hz), 10.53(1H, s), 12.18 (1H, brs)

[α]_(D) ²⁵ +114.7 (c 0.2505, MeOH)

Example 11trans-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylic acid (Step 1)

A mixture of dibenzyl trans-cyclobutane-1,3-dicarboxylate (100 mg, 0.31mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50%, wet) in MeOH (2.0mL) was stirred at room temperature for hr under hydrogen atmosphere (1atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give crudetrans-cyclobutane-1,3-dicarboxylic acid as a colorless oil.

(Step 2)

HATU (124 mg, 0.32 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.27 mmol), DIEA (0.093 mL, 0.54 mmol) and the crudetrans-cyclobutane-1,3-dicarboxylic acid (58.5 mg, 0.41 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)) to give the title compound (24.0 mg, 0.048 mmol, 17.89%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (6H, s), 1.81-1.93 (2H, m), 2.28-2.47(4H, m), 2.77-3.03 (5H,m), 3.44-3.60 (1H, m), 3.60-3.74 (1H, m), 3.82(3H, s), 3.86-3.99 (1H, m), 5.72 (1H, s), 6.72 (1H, d, J=8.7 Hz),7.10-7.29 (2H, m), 7.79 (1H,d J=8.7 Hz), 10.54 (1H, s), 12.26 (1H, brs)

Example 12trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutanecarboxylicacid

HATU (234 mg, 0.61 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(200 mg, 0.51 mmol), DIEA (0.175 mL, 1.02 mmol) andtrans-cyclobutane-1,3-dicarboxylic acid (111 mg, 0.77 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)) to give the title compound (32.1 mg, 0.062 mmol, 12.13%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.24-0.36 (9H, m), 2.23-2.47 (4H, m),2.68-2.98 (2H, m), 2.98-3.13 (1H, m), 3.35-3.56 (2H, m), 3.67-3.75 (3H,m), 3.77-3.93 (1H, m), 5.61 (1H, s), 6.75-6.87 (2H, m), 7.14-7.27 (2H,m), 7.38-7.53 (1H, m), 10.82 (1H, s), 12.30 (1H, brs)

Example 13((1R,2S)-2-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)aceticacid (Step 1)

1N Sodium hydroxide (81 mL, 81.36 mmol) was added to a solution ofdiethyl trans-cyclopropane-1,2-dicarboxylate (15.15 g, 81.36 mmol) inEtOH (100 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr.The reaction mixture was concentrated under reduced pressure, 2Mhydrochloric acid and NaCl were added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→100% ethyl acetate/hexane) to givetrans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (11.20 g, 70.8 mmol,87%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.28 (3H,t,J=7.2 Hz), 1.41-1.55 (2H, m),2.12-2.28 (2H, m), 4.12-4.20 (2H, m) (The peak derived from COOH was notobserved).

(Step 2)

1M Borane-THF complex THF solution (85 mL, 84.98 mmol) was added to asolution of trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (11.2 g,70.82 mmol) in THF (100 mL) at 0° C., and the mixture was stirredovernight at room temperature. MeOH was added thereto, and then the gaswas not generated. The reaction mixture was concentrated under reducedpressure. The residue was dissolved in DMF (50 mL),tert-butylchlorodiphenylsilane (20.10 mL, 84.98 mmol) and imidazole(5.79 g, 84.98 mmol) were added thereto, and the mixture was stirred for5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, and concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→35% ethyl acetate/hexane) to giveethyltrans-2-((tert-butyldiphenylsilyloxy)methyl)cyclopropanecarboxylate(21.40 g, 55.9 mmol, 79%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.81-0.94 (1H, m), 1.04 (9H, s), 1.08-1.18(1H, m), 1.20-1.32 (3H, m), 1.51-1.59 (1H, m), 1.60-1.71 (1H, m),3.55-3.62 (1H, m), 3.66-3.75 (1H, m), 4.12 (2H,q,J=7.2 Hz), 7.32-7.45(6H, m), 7.58-7.72 (4H, m)

(Step 3)

To a suspension of LAH (0.92 g, 24.24 mmol) in THF (100 mL) was added asolution of ethyltrans-2-((tert-butyldiphenylsilyloxy)methyl)cyclopropanecarboxylate(21.4 g, 55.94 mmol) in THF (20 mL) at 0° C., and the mixture wasstirred for 2 hr. To the reaction mixture were added successively water(0.92 mL), 15% aqueous sodium hydroxide solution (0.92 mL) and water(2.76 mL). The precipitate was removed by filtration, and the filtratewas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 1→30%ethyl acetate/hexane) to givetrans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (14.16g, 41.66 mmol, 74%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.31-0.53 (2H,m), 0.89-1.01 (2H,m), 1.02-1.10(9H, m), 1.21-1.26 (1H, m), 3.34-3.52 (3H, m), 3.69 (1H, dd, J=10.8, 5.5Hz), 7.32-7.46 (6H, m), 7.61-7.73 (4H, m)

(Step 4)

TEA (0.450 mL, 3.23 mmol) was added to a mixture oftrans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (1 g,2.94 mmol), methanesulfonyl chloride (0.250 mL, 3.23 mmol) and THF (10mL) at 0° C., and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to givetrans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methylmethanesulfonate (1.230 g, 2.94 mmol, 100%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.50-0.66 (2H, m), 1.04 (9H, s), 1.06-1.19(2H, m), 2.99 (3H, s), 3.44-3.57 (1H, m), 3.71 (1H,dd,J=11.0,4.9 Hz),4.08 (2H, d, J=7.2 Hz), 7.32-7.48 (6H, m), 7.65 (4H, dd, J=7.0, 0.9 Hz).

(Step 5)

A mixture oftrans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methylmethanesulfonate (1.23 g, 2.94 mmol), potassium cyanide (0.383 g, 5.88mmol) and DMF (10 mL) was stirred overnight at 60° C. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→60% ethyl acetate/hexane) to givetrans-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)acetonitrile(0.970 g, 2.78 mmol, 94%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.41-0.64 (2H, m), 0.83-0.94 (1H, m),0.96-1.06 (10H, m), 2.21-2.47 (2H, m), 3.48 (1H, dd, J=11.0, 6.0 Hz),3.71 (1H,dd,J=10.8,5.1 Hz), 7.33-7.45 (6H, m), 7.61-7.69 (4H, m).

(Step 6)

8M Aqueous sodium hydroxide solution (1 mL) was added to a mixture oftrans-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)acetonitrile(100 mg, 0.29 mmol) in EtOH (2 mL) and water (1 mL), and the mixture wasstirred at 80° C. for 5 hr. The reaction mixture was allowed to becooled to room temperature, and washed with toluene. The aqueous layerwas acidified with 6M hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was dried over sodium sulfate, andthe solvent was evaporated under reduced pressure to givetrans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50.0 mg, 0.384 mmol,134%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.41-0.66 (2H, m), 0.81-1.04 (2H, m),1.93-2.16 (2H, m), 2.67 (1H, dd, J=17.4, 5.3 Hz), 3.18 (1H, dd, J=11.1,8.5 Hz), 3.79 (1H, dd, J=11.0, 5.3 Hz) (The peak derived from COOH wasnot observed).

(Step 7)

A mixture of trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50 mg,0.38 mmol), benzyl bromide (0.050 mL, 0.42 mmol), potassium carbonate(58.4 mg, 0.42 mmol) and DMF (2 mL) was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→80% ethyl acetate/hexane) to givebenzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44.0 mg, 0.200mmol, 52%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.41-0.62 (2H, m), 0.83-1.03 (2H, m),1.98-2.13 (2H, m), 2.64 (1H, dd, J=16.8, 5.1 Hz), 3.17(1H,ddd,J=11.1,8.1,3.4 Hz), 3.74 (1H,ddd,J=10.9,7.5,5.5 Hz), 5.07-5.21(2H, m), 7.30-7.43 (5H, m).

(Step 8)

Sodium metaperiodate (107 mg, 0.50 mmol) and ruthenium(IV) oxide hydrate(3.02 mg, 0.02 mmol) were added to a solution of benzyltrans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44 mg, 0.20 mmol) inacetone (1 mL) and water (1 mL) at 0° C., and the mixture was stirred at0° C. to room temperature for 1 hr. The reaction mixture was filteredthrough Celite (while washing with acetone), and the filtrate wasconcentrated under reduced pressure. The residue was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid(46.0 mg, 0.196 mmol, 98%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.90 (1H, ddd, J=8.3, 6.4, 4.5 Hz), 1.28-1.38(1H, m), 1.52 (1H,dt,J=8.5,4.4 Hz), 1.80 (1H,dqd,J=8.9,6.9,4.2 Hz), 2.40(2H, d, J=7.2 Hz), 5.15 (2H, s), 7.30-7.41 (5H, m) (The peak derivedfrom COOH was not observed).

(Step 9)

T3P (3.84 mL, 6.45 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.326 g, 4.3 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.866g, 4.30 mmol), DIEA (3.74 mL, 21.50 mmol) and DMAP (0.578 g, 4.73 mmol)in ethyl acetate (31 mL) at room temperature, and the mixture wasstirred at 65° C. for 15 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate (×3). The organic layerwas washed with 10% aqueous citric acid solution, aqueous sodiumhydrogencarbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The precipitatewas washed with cooled, hexane to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.69 g, 3.44 mmol, 80%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ0.33 (9H, t, J=1.3 Hz), 1.54 (9H, s),2.83-3.02 (2H, m), 3.47 (1H, brs), 3.92 (3H, s), 3.98-4.09 (1H, m), 5.58(1H, brs), 6.64 (1H, d, J=8.3 Hz), 6.98-7.06 (2H, m), 7.46 (1H, brs),9.06 (1H, brs).

(Step 10)

tert-Butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.69 g) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(750 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(750 mg, >99% ee), as a white solid, respectively.

purification condition by chiral column chromatography

column: CHIRALPAK AD(NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 11)

Cooled TFA (10.5 mL) was added to tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(747 mg, 1.52 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 min. The reaction mixture was poured into ice andaqueous sodium hydrogencarbonate solution, and the pH of the mixture wasadjusted to 8 with aqueous sodium hydrogencarbonate solution. Then, themixture was extracted with ethyl acetate (×3). The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(567 mg, 1.448 mmol, 95%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.32 (9M,t,J=1.3 Hz), 1.66 (1H, brs),2.74-2.97 (2H, m), 3.11-3.29 (2H, m), 3.90 (3H, s), 4.58 (1H, s), 6.61(1M,d,J=8.3 Hz), 7.05-7.13 (2H, m), 7.80 (1H,d,J8.3 Hz), 9.60 (1H, s).

(Step 12)

HATU (137 mg, 0.36 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(128 mg, 0.33 mmol),trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (84 mg,0.36 mmol) and DIEA (0.065 mL, 0.36 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→80% ethyl acetate/hexane) to givebenzyl2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(46 mg, 0.076 mmol, 23%) as a less polar compound, and benzyl2-((1S,2R)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(39 mg, 0.064 mmol, 20%) as a more polar compound, respectively.

MS spectrum of benzyl2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetateMS(API): Calculated 607.7, Found 606.1 (M-H). MS spectrum of benzyl2-((1S,2R)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetateMS(API): Calculated 607.7, Found 606.1 (M-H).

(Step 13)

A mixture of benzyl2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(46 mg, 0.08 mmol) and 10% palladium-carbon (8.06 mg, 0.08 mmol, 50%,wet) in MeOH (15 mL) was stirred at room temperature for 1 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 30→100% ethyl acetate/hexane) to give the title compound (30.6mg, 0.059 mmol, 78%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 0.76 (1H, t, J=8.9 Hz),0.92-1.10 (1H, m), 1.44 (1H, brs), 2.08 (1H,dt,J=8.2,4.4 Hz), 2.16-2.29(2H, m), 2.39 (1H, dd, J=16.6, 6.4 Hz), 2.83-3.14 (2H, m), 3.84 (3H, s),3.98-4.37 (2H, m), 5.76 (1H, s), 6.73 (1H, d, J=8.7 Hz), 7.21 (2H, d,J=9.8 Hz), 7.70-7.85 (1H, m), 10.82 (1H, s), 12.16 (1H, brs).

[α]_(D) ²⁵ +121.9 (c 0.2520, MeOH)

Example 14(2-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)aceticacid

A mixture of benzyl2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate(46 mg, 0.08 mmol) and 10% palladium-carbon (8.06 mg, 0.08 mmol, 50%,wet) in MeOH (15 mL) was stirred at room temperature for 2 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 30→100% ethyl acetate/hexane) to give the title compound (31.2mg, 0.060 mmol, 80%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 0.61-0.78 (1H, m), 0.95-1.15(1H, m), 1.29-1.44 (1H, m), 2.05 (1H,dt,J=8.2,4.4 Hz), 2.27-2.39 (2H,m), 2.82-2.97 (1H, m), 3.02-3.21 (1H, m), 3.67-3.90 (3H, m), 3.95-4.17(1H, m), 4.18-4.35 (1H, m), 5.55-5.75 (1H, m), 6.73 (1H, d, J=8.7 Hz),7.07-7.35 (2H, m), 7.64-7.88 (1H, m), 10.67-10.94 (1H, m), 12.17 (1H,brs).

Example 15(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

A mixture of 3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylicacid (3.4 g, 16.02 mmol) and 10% palladium-carbon (100 mg, 0.94 mmol,50%, wet) in MeOH (30 mL) was stirred at room temperature for 5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 30→100% ethyl acetate/hexane) to give3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (3.40 g, 15.87mmol, 99%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.35-1.46 (9H, m), 1.90-2.10 (2H, m),2.27-2.87 (5H, m), 2.96-3.21 (1H, m) (The peak derived from COOH was notobserved).

(Step 2)

DEAD (7.23 mL, 15.87 mmol) was added to a solution of3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (3.4 g, 15.87mmol), PPh₃ (4.16 g, 15.87 mmol) and (R)-1-phenylethanol (1.904 mL,15.87 mmol) in THF (20 mL) at 0° C., and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (solvent gradient; 5→65% ethylacetate/hexane), and then again silica gel column chromatography(solvent gradient; 10→70% ethyl acetate/hexane) to give a mixture (2.7g) of two diastereomeric isomers as an oil.

¹H NMR (300 MHz, CDCl₃): δ1.38-1.45 (9H, m), 1.49-1.55 (3H, m),1.85-2.07 (2H, m), 2.22-2.84 (5H, m), 2.90-3.22 (1H, m), 5.77-5.96 (1H,m), 7.27-7.39 (5H, m).

The obtained oil (2.7 g) was subjected to chiral column chromatographyto resolve the mixture of the diastereomeric isomers. The fractionhaving a shorter retention time was concentrated togive(S)-1-phenylethylcis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (1.8 g, 5.65mmol, 67%), and the fraction having a longer retention time wasconcentrated to give (S)-1-phenylethyltrans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (0.4 g, 1.256mmol, 15%), respectively.

NMR spectrum of (S)-1-phenylethylcis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate

¹H NMR (300 MHz, CDCl₃): δ1.42 (9H, s), 1.52 (3H, d, J=6.8 Hz),1.83-2.05 (2H, m), 2.24-2.46 (4H, m), 2.48-2.68 (1H, m), 2.89-3.11 (1H,m), 5.86 (1H,q,J=6.8 Hz), 7.28-7.40 (5H, m).

NMR spectrum of (S)-1-phenylethyltrans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate

¹H NMR (300 MHz, CDCl₃): δ1.42 (9H, s), 1.53 (3H,d,J=6.4 Hz), 1.89-2.08(2H, m), 2.30-2.54 (4H, m), 2.61-2.85 (1H, m), 3.13(1H,ttd,J=9.4,5.9,1.1 Hz), 5.90 (1H,q,J=6.4 Hz), 7.27-7.38 (5H, m).

purification condition by chiral column chromatography

column: CHIRALPAK AD(AF003) 50 mmID×500 mmL

solvent: hexane/EtOH=980/20

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

A mixture of (S)-1-phenylethylcis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (1.8 g, 5.65mmol) and 10% palladium-carbon (0.602 g, 5.65 mmol, 50% wet) in MeOH (20mL) was stirred at room temperature for 2 hr under hydrogen atmosphere(1 atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to givecis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (1.200 g,5.60 mmol, 99%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.43 (9H, s), 1.92-2.10 (2H, m), 2.29-2.48(4H, m), 2.48-2.78 (1H, m), 2.93-3.16 (1H, m) (The peak derived fromCOOH was not observed).

(Step 4)

A solution of HATU (125 mg, 0.33 mmol),(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(110 mg, 0.30 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (70.2 mg,0.33 mmol) and DIEA (0.059 mL, 0.33 mmol) in DMF (2 mL) was stirredovernight at room temperature. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl2-(cis-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(150 mg, 0.265 mmol, 89%) as a colorless oil.

MS(API): Calculated 565.7, Found 564.2 (M-H).

(Step 5)

tert-Butyl2-(cis-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(150 mg, 0.27 mmol) was dissolved in TFA (2 mL), and the solution wasstirred at room temperature for 30 min. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 30→100%ethyl acetate/hexane) to give the title compound (135 mg, 0.265 mmol,100%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (6H, s), 1.67-1.97 (4H, m), 2.16-2.41(5H, m), 2.42-2.58 (1H, m), 2.76-3.06 (4H, m), 3.34-3.47 (1H, m),3.68-3.87 (3H, m), 3.88-4.10 (1H, m), 5.39-5.77 (1H, m), 6.72 (1H, d,J=8.7 Hz), 7.09-7.34 (2H, m), 7.64-7.89 (1H, m), 10.37-10.68 (1H, m),11.99 (1H, s).

[α]_(D) ²⁵ +113.5 (c 0.2510, MeOH)

Example 17(cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetic acid (Step 1)

Iodoethane (7.12 mL, 88.37 mmol) was added to a solution of 1-ethyl2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(14.2 g, 44.19 mmol) and cesium carbonate (18.72 g, 57.44 mmol) in DMF(100 mL), and the mixture was stirred at room temperature for 2.5 hr. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give 1-ethyl 2-tert-butyl6-ethoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (13.0 g, 37.2mmol, 84%) as a colorless oil.

(Step 2)

2N Aqueous sodium hydroxide solution (55.8 mL, 111.61 mmol) was added toa solution of 1-ethyl 2-tert-butyl6-ethoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (13.0 g, 37.20mmol) in a mixed solvent of EtOH (100 mL) and THF (100 mL), and themixture was stirred overnight at room temperature. To the reactionmixture was added ice water, and the mixture was washed with diethylether. The pH of the mixture was adjusted to 4 with 2N hydrochloricacid. Then, the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (3.56 g, 11.08 mmol, 29.8%) as a colorless oil.

(Step 3)

T3P (9.88 mL, 16.80 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.8 g, 5.60 mmol),3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (1.206 g, 5.60mmol), DIEA (4.89 mL, 28.01 mmol) and DMAP (0.684 g, 5.60 mmol) in ethylacetate (5 mL), and the mixture was stirred overnight at 60° C. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with 10% aqueous citric acidsolution, aqueous sodium hydrogencarbonate solution and brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.380 g, 4.59 mmol, 82%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.38-1.44 (9H,m), 1.51 (9H,s,), 2.71-2.99 (2H,m), 3.30 (3H, s), 3.51 (2H, s), 3.54-3.76 (2H, m), 4.03 (2H,q,J=6.8 Hz),5.55 (1H, brs), 6.72 (1H, s), 6.80 (1H, dd, J=8.5, 2.5 Hz), 7.03 (2H, d,J=12.5 Hz), 7.14 (1H, brs), 8.89 (1H, s).

(Step 4)

tert-Butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.20 g) was subjected to optical resolution by chiralcolumn chromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.02 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(5)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.03 g, 98.7% ee), as a white solid, respectively.

purification condition by chiral column chromatography

column: CHIRALCEL OD(NL001) 50 mmID×500 mmL

solvent: hexane/EtOH-900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

4N Hydrogen chloride/ethyl acetate (5 mL) was added to a solution oftert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.02 g, 1.97 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the precipitate was collected by filtrationwith hexane to give(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.917 g, 2.016 mmol, 102%) as a white solid.

MS(API): Calculated 454.9, Found 419.4 (M-HCl+H).

(Step 6)

HATU (113 mg, 0.30 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (123 mg, 0.27 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.7 mg,0.30 mmol) and DIEA (0.107 mL, 0.59 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give tert-butyl(cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate(166 mg, 0.270 mmol, 100%).

MS(API): Calculated 614.7, Found 613.2 (M-H).

(Step 7)

Cooled TFA (2 mL) was added to tert-butyl(cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate(166 mg, 0.27 mmol) at 0° C., and the mixture was stirred at 0° C. for30 min. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givethe title compound (134 mg, 0.240 mmol, 89%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (3H,t, J=7.0 Hz), 1.36 (6H, s),1.73-1.93 (2H, m), 2.20-2.40 (5H, m), 2.67-2.84 (1H, m), 2.96-3.12(1H,m), 3.19 (3H, s), 3.27-3.39 (1H, m), 3.40-3.53 (3H, m), 3.86-4.03(3H, m), 5.30-5.62 (1H,m), 6.67-6.88 (2H, m), 7.06-7.28 (2H, m),7.35-7.53 (1H, m), 10.48-10.77 (1H, m), 11.98 (1H, brs).

Example 18(cis-3-(((1R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

Sodium hydride (60%, oil, 1.726 g, 43.15 mmol) was added to a solutionof2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(7.62 g, 17.26 mmol) and iodoethane (3.49 mL, 43.15 mmol) in DMF (30 mL)at 5° C., and the mixture was stirred at room temperature for 14 hr. Tothe reaction mixture was added aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate (×2). The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 5→20% ethylacetate/hexane) to give4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(8.51 g, 18.12 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.14 (3H, t, J=7.0 Hz), 1.39 (6H, t, J=2.1Hz), 3.47 (2H,d,J=7.2 Hz), 3.53 (2H, s), 3.79 (6H, s), 4.46 (4H, s),6.17 (2H, d, J=14.4 Hz), 6.79-6.91 (4H, m), 7.11 (4H, d, J=8.7 Hz).

(Step 2)

A mixture of4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(8.51 g, 18.12 mmol), 1N hydrochloric acid (36.2 mL) and 10%palladium-carbon (1.929 g, 0.91 mmol, 50%, wet) in MeOH (164 mL) underhydrogen atmosphere (4 atm), and the mixture was stirred at roomtemperature for 1.5 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas dissolved in ethyl acetate, and the solution was washed with 1Naqueous sodium hydroxide solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→20% ethyl acetate/hexane) to give4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (3.87 g, 16.88mmol, 93%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.13 (3H, t, J=7.0 Hz), 1.40 (6H, t, J=2.5Hz), 3.40-3.50 (2H, m, J=7.2, 7.2, 7.2 Hz), 3.53 (2H, s), 3.57-3.87 (2H,m), 6.09 (1H, s), 6.13 (1H, s).

(Step 3)

T3P (4.62 mL, 7.85 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (841 mg, 2.62 mmol),4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62mmol), DIEA (2.285 mL, 13.09 mmol) and DMAP (320 mg, 2.62 mmol) in ethylacetate (5 mL), and the mixture was stirred at 60° C. overnight. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give tert-butyl6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(700 mg, 1.314 mmol, 50.2%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ1.10 (3H,t,J=7.0 Hz), 1.36-1.45 (9H, m), 1.51(9H, s), 2.76-2.98 (2H, m), 3.44 (2H,q,J=6.8 Hz), 3.54 (3H, s),3.62-3.78 (1M,m), 4.03 (2H,q,J=6.8 Hz), 5.55 (1H, brs), 6.71 (1H, d,J=2.3 Hz), 6.80 (1M,dd,J=8.3,2.6 Hz), 6.95-7.08 (2H, m, J=12.5 Hz),7.10-7.22 (1M,m), 8.92 (1H, s).

(Step 4)

tert-Butyl6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.70 g) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.32 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(5)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.32 g, 92.2% ee), as a white solid, respectively.

purification condition by chiral column chromatography

column: CHIRALPAK IA(QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(320 mg, 0.60 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the precipitate was collected by filtrationwith hexane to give(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (273 mg, 0.582 mmol, 97%) as a white solid.

MS(API): Calculated 468.96, Found 433.4 (M-HCl+H).

(Step 6)

HATU (90 mg, 0.24 mmol) was added to a solution of(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (101 mg, 0.22 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (50.8 mg,0.24 mmol) and DIEA (0.085 mL, 0.47 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl2-(cis-3-((R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(135 mg, 0.215 mmol, quant.).

MS(API): Calculated 628.8, Found 627.2 (M-H).

(Step 7)

Cooled TFA (2 mL) was added to tert-butyl2-(cis-3-((R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(179 mg, 0.28 mmol) at 0° C., and the mixture was stirred at 0° C. for30 min. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givethe title compound (108 mg, 0.189 mmol, 66.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.02 (3H, t, J=7.0 Hz), 1.29 (3H,t,J=7.0Hz), 1.36 (6H, s), 1.71-1.92 (2H, m), 2.16-2.38 (5H, m), 2.50(1H,dt,J=3.5,1.8 Hz), 2.71-2.81 (1H, m), 2.95-3.13 (1H, m), 3.29-3.54(5H, m), 3.82-4.10 (3H, m), 5.35-5.64 (1H, m), 6.70-6.88 (2H, m), 7.18(2H, d, J=13.6 Hz), 7.35-7.50 (1H, m), 10.45-10.79 (1H, m), 12.00 (1H,brs).

[α]_(D) ²⁵ +11.0 (c 0.2520, MeOH)

Example 19(cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

To a mixture of 1-ethyl 2-tert-butyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (5 g, 15.56mmol), DIEA (5.43 mL, 31.12 mmol), DMAP (0.190 g, 1.56 mmol) and THF (30mL) was added1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(8.34 g, 23.34 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 hr. To the reaction mixture was added ethylacetate, the mixture was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane), and thensilica gel column chromatography (NH, solvent gradient; 3→50% ethylacetate/hexane) to give 1-ethyl 2-tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.44 g, 16.41 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.21-1.31 (3H,m), 1.45-1.53 (9H,m), 2.82-2.99(2H, m), 3.60-3.77 (1H, m), 3.80-3.99 (1H, m), 4.18 (2H,q,J=7.2 Hz),5.28-5.69 (1H, m), 7.01-7.19 (2H, m), 7.60 (1H, dd, J=8.7, 3.8 Hz).

(Step 2)

A mixture of 1-ethyl 2-tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.44 g, 16.41 mmol), Pd(PPh₃)₄ (0.948 g, 0.82 mmol), zinc cyanide(2.119 g, 18.05 mmol) and DMF (100 mL) was stirred overnight at 100° C.The reaction mixture was diluted with ethyl acetate, and filtered. Thefiltrate was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 3→60% ethyl acetate/hexane) to give 1-ethyl2-tert-1-butyl 6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(4.92 g, 14.89 mmol, 91%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.18-1.33 (3H, m), 1.42-1.53 (9H, m),2.78-3.03 (2H, m), 3.62-3.78 (1H, m), 3.80-3.99 (1H, m), 4.18(2H,q,J=7.1 Hz), 5.38-5.71 (1H, m), 7.40-7.55 (2H, m), 7.58-7.69 (1H,m).

(Step 3)

To a solution of 1-ethyl 2-tert-butyl6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.5 g, 1.51 mmol)in acetic acid (5.00 mL) and pyridine (10 mL) was added a mixture ofRaney-nickel (0.5 g, 1.51 mmol) and water (5 mL), and then sodiumhypophosphite monohydrate (2.5 g, 23.59 mmol) was added thereto underargon atmosphere. The mixture was stirred at 60° C. for 3 hr, and thenovernight at 100° C. The reaction mixture was filtered through Celite,and the filtrate was diluted with ethyl acetate. The mixture was washedwith aqueous ammonium chloride solution, aqueous sodiumhydrogencarbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→70% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.430 g, 1.290mmol, 85%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.26 (3H,t,J=7.2 Hz), 1.45-1.53 (9H, m),2.80-3.13 (2H, m), 3.63-3.97 (2H, m), 4.18 (2H,q,J=7.2 Hz), 5.44-5.72(1H, m), 7.61-7.80 (3H, m), 9.99 (1H, s).

(Step 4)

To a solution of 1-ethyl 2-tert-butyl6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (430 mg, 1.29mmol) in MeOH (10 mL) was added sodium borohydride (24.40 mg, 0.64 mmol)at 0° C., and the mixture was stirred for 20 min. To the reactionmixture was added aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give 1-ethyl 2-tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg,1.163 mmol, 90%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.23-1.30 (3H, m), 1.37-1.51 (9H, m), 1.67(1H, brs), 2.70-3.05 (2H, m), 3.66-3.84 (2H, m), 4.11-4.21 (2H, m), 4.67(2H, s), 5.28-5.64 (1H, m), 7.13-7.25 (2H, m), 7.44-7.54 (1H, m).

(Step 5)

To a mixture of 1-ethyl 2-tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg,1.16 mmol), methanesulfonyl chloride (0.135 mL, 1.74 mmol) and THF (10mL) was added TEA (0.243 mL, 1.74 mmol) at 0° C., and the mixture wasstirred for 1 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give 1-ethyl 2-tert-butyl6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(500 mg, 1.209 mmol, 104%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.20-1.30 (3H, m), 1.44-1.51 (9H, m),2.78-3.05 (5H, m), 3.70-3.92 (2H, m), 4.16 (2H,q,J=7.2 Hz), 5.20 (2H,s), 5.37-5.65 (1H, m), 7.20-7.30 (2H, m), 7.49-7.59 (1H, m).

(Step 6)

To a solution of 1-ethyl 2-tert-butyl6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(500 mg, 1.21 mmol) in MeOH (5 mL) was added TEA (0.337 mL, 2.42 mmol),and the mixture was stirred at 70° C. for 2 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 3→60%ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (169 mg,0.484 mmol, 40.0%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.20-1.30 (3H, m), 1.43-1.53 (9H, m),2.73-3.06 (2H, m), 3.40 (3H, s), 3.67-3.84 (2H, m), 4.14 (2H,q,J=7.2Hz), 4.42 (2H, s), 5.22-5.64 (1H, m), 7.05-7.22 (2H, m), 7.42-7.56 (1H,m).

(Step 7)

To a solution of 1-ethyl 2-tert-butyl6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (160 mg,0.46 mmol) in a mixture of MeOH (5 mL), THF (5.00 mL) and water (5.00mL) was added lithium hydroxide (65.8 mg, 2.75 mmol), and the mixturewas stirred at 60° C. for 1 hr. The reaction mixture was concentratedunder reduced pressure. The obtained residue was dissolved in water, andthe solution was washed with ethyl acetate. The pH of the aqueous layerwas adjusted to 3 with 1M hydrochloric acid, and the mixture wasextracted with ethyl acetate (×3). The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (148 mg, 0.461 mmol, 101%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.35-1.57 (9H, m), 2.77-3.02 (2H,m), 3.39 (3H,s), 3.60-3.90 (2H, m), 4.42 (2H, s), 5.23-5.66 (1H,m), 7.07-7.22 (2H,m), 7.45 (1H, d, J=7.6 Hz) (The exchangeable 1H was not observed).

(Step 8)

T3P (8.24 mL, 14.00 mmol) was added to a mixture of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.5 g, 4.67 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.837 g, 4.67 mmol),DIEA (4.08 mL, 23.34 mmol), DMAP (0.570 g, 4.67 mmol) and ethyl acetate(5 mL) at 60° C., and the mixture was stirred at 60° C. for 2 days. Tothe reaction mixture was added ethyl acetate, and the mixture was washedwith water and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 32→340% ethylacetate/hexane) to give tert-butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.600 g, 3.32 mmol, 71.0%) as a white solid.

MS(API): Calculated 482.6, Found 481.3 (M-H).

(Step 9)

tert-Butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.60 g) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.77 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.73 g, >99% ee), respectively.

purification condition by chiral column chromatography

column: CHIRALCEL OD(NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 10)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.77 g, 1.60 mmol) in ethyl acetate (2 Tali), and the mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated, and the obtained precipitate was washed with ethylacetate/hexane to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.730 g, 1.743 mmol, 109%) as a white solid.

MS(API): Calculated 418.9, Found 381.2 (M-HCl−H).

(Step 11)

A mixture of HATU (100 mg, 0.26 mmol),(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.24 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (56.3 mg,0.26=1), DIEA (0.094 mL, 0.53 mmol) and DMF (2 mL) was stirred overnightat room temperature. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→4.50% ethyl acetate/hexane) to givetert-butyl2-(cis-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(130 mg, 0.225 mmol, 94%) as a colorless oil.

MS(API): Calculated 578.7, Found 577.2 (M-H).

(Step 12)

tert-Butyl2-(cis-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(130 mg, 0.22 mmol) was dissolved in TFA (2 mL) at 0° C., and thesolution was stirred for 30 min. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (solvent gradient; 50→100% ethylacetate/hexane) to give the title compound (106 mg, 0.203 mmol, 90%) asa colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.28 (3H, s), 1.28 (3H, s), 1.70-1.94 (4H,m), 2.12-2.40 (4H, m), 2.76-2.91 (3H, m), 2.96-3.14 (1H, m), 3.22-3.28(3H, m), 3.29-3.41 (1H, m), 3.49-3.53 (1H, m), 3.85-4.01 (1H, m), 4.35(2H, s), 5.44-5.84 (1H, m), 7.01-7.31 (4H, m), 7.51 (1H, d, J=8.7 Hz),10.21-10.61 (1H, m), 11.98 (1H, s).

[α]_(D) ²⁵ +31.5 (c 0.2530, MeOH)

Example 20(trans-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

A mixture of (S)-1-phenylethyltrans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (0.4 g, 1.26mmol) and 10% palladium-carbon (0.134 g, 1.26 mmol, 50%, wet) in MeOH(20 mL) was stirred at room temperature for 1.5 hr under hydrogenatmosphere (1 atm). The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure to givetrans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (0.261 g,1.218 mmol, 97%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.36-1.47 (9H, m), 1.96-2.11 (2H, m), 2.39(2H, d, J=7.6 Hz), 2.43-2.57 (2H, m), 2.69-2.88 (1H, m), 3.03-3.26 (1H,m) (The peak derived from COOH was not observed).

(Step 2)

HATU (113 mg, 0.30 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.27 mmol),trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.8 mg,0.30 mmol) and DIEA (0.053 mL, 0.30 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give tert-butyl2-(trans-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(150 mg, 0.27 mmol, 98%) as a. colorless oil.

MS(API): Calculated 565.7, Found 564.2 (M-H).

(Step 3)

Cooled TFA (2 mL) was added to tert-butyl2-(trans-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(150 mg, 0.27 mmol) at 0° C., and the mixture was stirred at 0° C. for30 min. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givethe title compound (113 mg, 0.222 mmol, 84%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.11-1.38 (7H, m), 1.74-2.07 (4H, m),2.22-2.47 (4H, m), 2.68-3.06 (4H, m), 3.55 (1H, d, J=8.7 Hz), 3.62-3.75(1H, m), 3.83 (3H, d, J=1.9 Hz), 3.85-4.11 (1H, m), 5.36-5.82 (1H, m),6.72 (1H, d, J=8.7 Hz), 7.10-7.32 (2H, m), 7.78 (1H, d, J=8.3 Hz),10.36-10.65 (1H, m), 12.03 (1H, brs).

[α]_(D) ²⁵ +109.0 (c 0.2515, MeOH)

Example 23(cis-3-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (107 mg, 0.28 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.26 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (60.2 mg,0.28 mmol) and DIEA (0.050 mL, 0.28 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give tert-butyl2-(cis-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(100 mg, 0.170 mmol, 66.6%) as a colorless oil.

MS(API): Calculated 587.7, Found 586.1 (M-H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl2-(cis-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(100 mg, 0.17 mmol) at 0° C., and the mixture was stirred at 0° C. for30 min. The pH of the reaction mixture was adjusted to 6 with cooledaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (67.0mg, 0.126 mmol, 74.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.74-1.97 (2H, m), 2.21-2.38(5H, m), 2.75-2.90 (1H, m), 2.91-3.05 (1H, m), 3.36-3.47 (1H, m),3.64-3.79 (1H, m), 3.82 (3H, s), 3.86-4.08 (1H, m), 5.48-5.76 (1H, m),6.73 (1H, d, J=8.3 Hz), 7.14-7.37 (2H, m), 7.63-7.85 (1H, m),10.61-10.97 (1H, m), 11.97 (1H, brs).

[α]_(D) ²⁵ +108.8 (c 0.2515, MeOH)

Example 24(trans-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (49.9 mg, 0.13 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (50 mg, 0.12 mmol),trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (26.9 mg,0.13 mmol) and DIEA (0.024 mL, 0.13 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the precipitate wascollected by filtration, and washed with water to give tert-butyl2-(trans-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(74.0 mg, 0.128 mmol, 107%) as a white solid.

MS(API): Calculated 578.7, Found 577.2 (M-H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl2-(trans-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(74 mg, 0.13 mmol) at 0° C., and the mixture was stirred at 0° C. for 30min. The pH of the reaction mixture was adjusted to 6 with cooledaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (51.0mg, 0.098 mmol, 76%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.28 (6H, d, J=1.5 Hz), 1.78-2.00 (4H, m),2.29-2.47 (5H, m), 2.75-2.93 (3H, m), 2.97-3.15 (1H, m), 3.24-3.28 (3H,m), 3.38-3.61 (2H, m), 3.72-4.01 (1H, m), 4.35 (2H, s), 5.71 (1H, s),7.06-7.30 (4H, m), 7.39-7.67 (1H, m), 10.36-10.65 (1H, m), 12.02 (1H,s).

[α]_(D) ²⁵ +28.3 (c 0.2510, MeOH)

Example 25(cis-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (92 mg, 0.24 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(86 mg, 0.22 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (51.9 mg,0.24 mmol) and DIEA (0.043 mL, 0.24 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give tert-butyl2-(cis-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(86 mg, 0.22 mmol) as a colorless oil.

MS(API): Calculated 586.7, Found 585.1 (M-H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl2-(cis-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(130 mg, 0.22 mmol) at 0° C., and the mixture was stirred at 0° C. for30 min. The pH of the reaction mixture was adjusted to 6 with cooledaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (78mg, 0.146 mmol, 65.9%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.70-1.94 (2H, m), 2.20-2.41(5H, m), 2.67-2.84 (1H, m), 2.97-3.13 (1H, m), 3.27-3.38 (1H, m), 3.45(1H, ddd, J=12.2, 8.4, 4.0 Hz), 3.72 (3H, s), 3.82-4.03 (1H, m),5.40-5.67 (1H, m), 6.74-6.94 (2H, m), 7.11-7.33 (2H, m), 7.36-7.54 (1H,m), 10.59-10.94 (1H, m), 11.99 (1H, s).

[α]_(D) ²⁵ +14.8 (c 0.2000, Meal)

Example 27(trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (55.7 mg, 0.15 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(52 mg, 0.13 mmol),trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (30.0 mg,0.14 mmol) and DIEA (0.026 mL, 0.15 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the precipitate wascollected by filtration, and washed with water to give tert-butyl2-(trans-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(64.0 mg, 0.109 mmol, 82%) as a white solid.

MS(API): Calculated 586.7, Found 585.1 (M-H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl2-(trans-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(64 mg, 0.11 mmol) at 0° C., and the mixture was stirred at 0° C. for 30min. The pH of the reaction mixture was adjusted to 6 with cooledaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (41.5mg, 0.078 mmol, 71.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.80-2.01 (2H, m), 2.27-2.39(2H, m), 2.41-2.48 (3H, m), 2.67-2.84 (1H, m), 2.96-3.14 (1H, m), 3.40(1H, ddd, J=12.3, 8.5, 4.2 Hz), 3.45-3.58 (1H, m), 3.72 (3H, s),3.78-3.97 (1H, m), 5.32-5.68 (1H, m), 6.72-6.90 (2H, m), 7.08-7.33 (2H,m), 7.37-7.52 (1H, m), 10.59-10.91 (1H, m), 12.03 (1H, s).

Example 28(trans-3-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (64.1 mg, 0.17 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(60 mg, 0.15 mmol),trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (32.8 mg,0.15 mmol) and DIEA (0.030 mL, 0.17 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the precipitate wascollected by filtration, and washed with water to give tert-butyl2-(trans-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(60.0 mg, 0.102 mmol, 66.6%) as a white solid.

MS(API): Calculated 587.7, Found 586.1 (M-H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl2-(trans-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate(60 mg, 0.10 mmol) at 0° C., and the mixture was stirred at 0° C. for 30min. The pH of the reaction mixture was adjusted to 6 to 7 with cooledaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50-4100% ethyl acetate/hexane) to give the title compound(36.0 mg, 0.068 mmol, 66.3%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.82-1.99 (2H, m), 2.29-2.48(5H, m), 2.75-2.90 (1H, m), 2.92-3.07 (1H, m), 3.47-3.61 (1H, m),3.61-3.74 (1H, m), 3.83 (3H, s), 3.91 (1H, ddd, J=12.8, 8.3, 4.5 Hz),5.41-5.76 (1H, m), 6.62-6.81 (1H, m), 7.11-7.29 (2H, m), 7.78 (1H, d,J=8.7 Hz), 10.61-10.97 (1H, m), 12.03 (1H, s).

[α]_(D) ²⁵ +104.6 (c 0.2525, MeOH)

Example 29((1R,2S)-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclopropyl)aceticacid (Step 1)

HATU (137 mg, 0.36 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(128 mg, 0.33 mmol),trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (84 mg,0.36 mmol) and DIEA (0.065 mL, 0.36 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane to give amixture (147 mg) of two diastereomeric isomers.

The obtained mixture (147 mg) of diastereomeric isomers was resolved bychiral column chromatography. The fraction having a shorter retentiontime was concentrated to give benzyl2-((1R,2S)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetate(55.4 mg, 0.091 mmol, 28%, >99% de), and the fraction having a longerretention time was concentrated to give benzyl2-((1S,2R)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetate(63 mg, 0.104 mmol, 32%, >99% de), respectively.

MS spectrum of benzyl2-((1R,2S)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetateMS(API): Calculated 606.7, Found 605.1 (M-H). MS spectrum of benzyl2-((1S,2R)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetateMS(API): Calculated 606.7, Found 605.2 (M-H).

purification condition by chiral column chromatography

column: CHIRALPAK AD(NF001) 50 mmID×500 mmL

solvent: EtOH

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2) A mixture of benzyl2-((1R,2S)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetate(55 mg, 0.09 mmol) and 10% palladium-carbon (9.65 mg, 0.09 mmol, 50%,wet) in MeOH (2 mL) was stirred at room temperature for 2 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (43.8mg, 0.085 mmol, 94%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.29 (9H, s), 0.67-0.81 (1H, m, J=4.5 Hz),0.86-1.08 (1H, m, J=4.5 Hz), 1.32-1.49 (1H, m), 1.94-2.06 (1H, m, J=3.4Hz), 2.17-2.30 (1H, m), 2.31-2.42 (1H, m), 2.78-2.94 (1H, m, J=15.1 Hz),3.06-3.22 (1H, m), 3.66-3.80 (4H, m), 4.16-4.31 (1H, m), 5.65 (1H, s),6.76-6.87 (2H, m), 7.19 (2H, d, J=9.4 Hz), 7.45 (1H,d,J=7.9 Hz), 10.76(1H, s), 12.12 (1H, brs).

[α]_(D) ²⁵ +30.8 (c 0.2515, MeOH)

Example 30((1S,2R)-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclopropyl)aceticacid

A mixture of benzyl2-((1S,2R)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetate(63 mg, 0.10 mmol) and 10% palladium-carbon (11.1 mg, 0.10 mmol, 50%,wet) in MeOH (20 mL) was stirred at room temperature for 2 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (40.0mg, 0.077 mmol, 74.6%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.29 (9H, s), 0.57-0.74 (1H, m), 1.00-1.11(1H, m), 1.31 (1H, brs), 1.93-2.04 (1H, m), 2.34 (2H, dd, J=6.8, 4.2Hz), 2.79-2.91 (1H, m), 3.20 (1H,t,J=9.4 Hz), 3.64-3.78 (4H, m),4.19-4.39 (1H, m), 5.51-5.68 (1H, m), 6.72-6.92 (2H,m), 7.10-7.32 (2H,m), 7.39-7.52 (1H, m), 10.67-10.83 (1H, m), 12.17 (1H, brs).

Example 31cis-3-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid

HATU (82 mg, 0.21 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) andcis-cyclobutane-1,3-dicarboxylic acid (38.7 mg, 0.27 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)) to give the title compound (35.6 mg, 0.069 mmol, 38.5%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.22-2.43 (4H, m), 2.76-2.92(1H, m), 2.92-3.08 (2H, m), 3.39-3.52 (1H, m), 3.66-3.79 (1H, m), 3.82(3H, s), 3.88-4.01 (1H, m), 5.67 (1H, s), 6.66-6.78 (1H, m), 7.14-7.27(2H, m), 7.66-7.88 (1H, m), 10.88 (1H, s), 12.21 (1H, brs)

[α]_(D) ²⁵ +101.5 (c 0.2510, MeOH)

Example 32cis-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutanecarboxylic acid (Step 1)

A solution of 1-chloro-2-fluoro-4-nitrobenzene (2.63 g, mmol), HMDS(8.12 g, 55.50 mmol) and Pd(PPh₃)₄ (0.433 g, 0.38 mmol) in xylene (6.5mL) was stirred at 200° C. for 1 hr under microwave irradiation. To thereaction mixture was added ethyl acetate (about 150 mL), and theinsoluble substance was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by NH-silica gel column chromatography (solvent gradient; 2→45%ethyl acetate/hexane) to give (2-fluoro-4-nitrophenyl)trimethylsilane(3.22 g, 15.10 mmol, 101%) a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.36 (9H, d, J=1.1 Hz), 7.57 (1H, dd, J=8.1,5.5 Hz), 7.82 (1H,dd,J=8.1,2.1 Hz), 7.99 (1H, dd, J=8.1, 2.1 Hz).

(Step 2)

A mixture of (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10mmol) and 10% palladium-carbon (1.0 g, 0.47 mmol, 50%, wet) in MeOH (65mL) was stirred at room temperature for 3.5 hr under hydrogen atmosphere(1 atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 2→15% MeOH/ethylacetate) to give 3-fluoro-4-(trimethylsilyl)aniline (1.89 g, 10.31 mmol,68.3%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.26 (9H, d, J=0.8 Hz), 3.79 (2H, brs), 6.31(1H,dd,J=10.6,2.3 Hz), 6.44 (1H, dd, J=7.9, 1.9 Hz), 7.13(1H,dd,J=7.9,6.8 Hz).

(Step 3)

T3P (4.46 mL, 7.50 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.537 g, 5 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.916 g,5.00 mmol), DIEA (4.35 mL, 25.00 mmol) and DMAP (0.672 g, 5.50 mmol) inethyl acetate (35 mL), and the mixture was stirred at 70° C. for 18 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate (×3). The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→20% ethyl acetate/hexane), and theprecipitate was washed with IPE/hexane to give tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.85 g, 3.91 mmol, 78%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, s), 1.52 (9H, s), 2.80-2.96 (2H, m),3.55-3.76 (2H, m), 3.80 (3H, s), 5.61 (1H, brs), 6.72 (1H,d,J=2.3 Hz),6.81 (1H, dd, J=8.3, 2.6 Hz), 7.09 (1H,d,J=7.9 Hz), 7.24-7.30 (2H, m),7.39 (1H, dd, J=10.6, 1.9 Hz), 9.00 (1H, brs).

(Step 4)

tert-Butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.10 g) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.53 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.51 g, 96.7% ee), as a white solid, respectively.

purification condition by chiral column chromatography

column: CHIRALCEL OD(NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (5.0 mL) was added to tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(526 mg, 1.11 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was poured into ice and aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by NH-silica gel columnchromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(350.3 mg, 0.940 mmol, 84%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, d, J=0.8 Hz), 2.68-2.82 (1H, m),2.83-2.97 (1H, m), 3.10-3.19 (2H, m), 3.79 (3H, s), 4.64 (1H, s), 6.65(1H, d, J=2.6 Hz), 6.79 (1H,dd,J=8.5,2.6 Hz), 7.18 (1H,dd,J=7.9,1.9 Hz),7.27 (1H, s), 7.46 (1H, dd, J=10.6, 1.9 Hz), 7.53 (1H, d, J=8.6 Hz),9.46 (1H, s)

(Step 6)

HATU (147 mg, 0.39 mmol) was added to a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(120 mg, 0.32 mmol), DIEA (0.110 mL, 0.64 mmol) andcis-cyclobutane-1,3-dicarboxylic acid (69.6 mg, 0.48 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane, 0→10%MeOH/ethyl acetate), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(47.0 mg, 0.094 mmol, 29.3%) as a white solid.

¹H NMR (300 MHz, DMSO-d₅): δ0.30 (9H, s), 2.22-2.43 (4H, m), 2.76-2.92(1H, m), 2.92-3.08 (2H, m), 3.39-3.52 (1H, m), 3.66-3.79 (1H, m), 3.82(3H, s), 3.88-4.01 (1H, m), 5.67 (1H, s), 6.66-6.78 (1H, m), 7.14-7.27(2H, m), 7.66-7.88 (1H, m), 10.88 (1H, s), 12.21 (1H, brs)

[α]_(D) ²⁵ +19.8 (c 0.2545, MeOH)

Example 33(cis-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (147 mg, 0.39 mmol) was added to a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(120 mg, 0.32 mmol), DIEA (0.110 mL, 0.64 mmol) andcis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (72.5 mg,0.34 mmol) in DMF (2.0 mL) at room temperature, and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→450%ethyl acetate/hexane) to give tert-butyl2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(162.1 mg, 0.285 mmol, 68%) as a white solid.

MS(API): Calculated 568.8, Found 567.2 (M-H).

(Step 2)

Cooled TFA (2.0 mL) was added to tert-butyl2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(160 mg, 0.28 mmol) at 0° C., and the mixture was stirred at 0° C. for 1hr. The reaction mixture was neutralized with ice and aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→4.90%ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(46.9 mg, 0.091 mmol, 32.5%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 1.73-1.93 (2H, m),2.20-2.39 (4H, m), 2.42-2.58 (1H, m), 2.68-2.84 (1H, m), 2.97-3.14 (1H,m), 3.22-3.39 (1H, m), 3.40-3.54 (1H, m), 3.72 (3H, s), 3.84-3.98(1H,m), 5.63 (1H, s), 6.72-6.89 (2H, m), 7.23-7.39 (2H, m), 7.40-7.56(2H, m), 10.64 (1H, s), 12.02 (1H, brs)

[α]_(D) ²⁵ +20.7 (c 0.2505, MeOH)

Example 34(trans-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

HATU (86 mg, 0.23 mmol) was added to a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.19 mmol), DIEA (0.064 mL, 0.38 mmol) andtrans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (42.3 mg,0.20 mmol) in DMF (2.0 mL) at room temperature, and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→50%ethyl acetate/hexane) to give tert-butyl2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(92.3 mg, 0.162 mmol, 86%) as a white solid.

MS(API): Calculated 568.8, Found 567.1 (M-H).

(Step 2)

Cooled TFA (2.0 mL) was added to tert-butyl2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(90 mg, 0.16 mmol) at 0° C., and the mixture was stirred at 0° C. for 1hr. The reaction mixture was neutralized with ice and aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→90%ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(29.8 mg, 0.058 mmol, 36.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.80-1.99 (2H, m), 2.24-2.40(2H,m), 2.40-2.47 (3H, m), 2.69-2.85 (1H, m), 2.98-3.14 (1H, m),3.37-3.57 (2H, m), 3.72 (3H, s), 3.79-3.96 (1H,m), 5.65 (1H, s),6.72-6.90 (2H, m), 7.22-7.39 (2H, m), 7.39-7.53 (2H, m), 10.65 (1H, s),12.03 (1H, brs)

Example 35(cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (Step 1)

Diethyl malonate (44.8 g, 280 mmol) was added to a suspension of sodiumhydride (60%, oil, 28.0 g, 700 mmol) in THF (280 mL) at 0° C., and themixture was stirred at room temperature for 1 hr. Then,1,2,3-trifluoro-5-nitrobenzene (24.79 g, 140 mmol) was added thereto at0° C., and the mixture was stirred at room temperature for 2 hr. To thereaction mixture was added aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate (×2). The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give diethyl2,6-difluoro-4-nitrophenylmalonate (42 g) as a colorless oil.

A solution of the obtained diethyl 2,6-difluoro-4-nitrophenylmalonate(42 g) in a mixed solvent of acetic acid (200 mL), water (150 mL) andconc. sulfuric acid (50 mL) was heated under reflux for 18 hr, and thereaction mixture was concentrated under reduced pressure. To the residuewas added water, and the mixture was extracted with ethyl acetate (×2).The organic layer was back-extracted with 10% sodium carbonate aqueoussolution, and the aqueous layer was acidified with 2N hydrochloric acid.The precipitate was collected by filtration to give2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128 mmol, 92.0%) aswhite crystals.

¹H NMR (300 MHz, DMSO-d₆): δ3.79 (2H, s), 7.81-8.24 (2H, m), 12.93 (1H,brs).

(Step 2)

A solution of 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128.5mmol) and conc. sulfuric acid (1.0 mL) in MeOH (260 mL) was heated underreflux for 18 hr. The reaction mixture was neutralized with aqueoussodium hydrogencarbonate solution, and ethyl acetate and water wereadded thereto. The organic layer was dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;0→100% ethyl acetate/hexane) to give methyl2-(2,6-difluoro-4-nitrophenyl)acetate (28.71 g, 128.5 mmol, 97.0%) as ayellow solid.

¹H NMR (300 MHz, CDCl₃): δ3.75 (3H, s), 3.80 (2H, s), 7.80-7.85 (2H, m).

(Step 3)

To a solution of methyl 2-(2,6-difluoro-4-nitrophenyl)acetate (10.7 g,50.20 mmol) and iodomethane (12.55 mL, 200.79 mmol) in DMF (100 mL) wasadded sodium hydride (60%, oil, 5.02 g, 125.49 mmol) at 0° C., and themixture was stirred at 0° C. for 4 hr. To the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20% ethyl acetate/hexane) to givemethyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate (12.10 g, 50.2mmol, 100%) as yellow crystals.

(Step 4)

A mixture of methyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate(3.2 g, 12.35 mmol) and 10% palladium-carbon (1.314 g, 0.617 mmol, 50%,wet) in MeOH (30 mL) was stirred overnight at room temperature underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give methyl2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.87 g, 12.52 mmol,101%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.59 (6H, t, J=1.7 Hz), 3.69 (3H, s), 3.77(2H, brs), 6.00-6.25 (2H, m).

(Step 5)

To a solution of methyl2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.8 g, 12.22 mmol)and α-chloro-4-methoxytoluene (3.48 mL, 25.65 mmol) in DMF (50 mL) wasadded sodium hydride (60%, oil, 1.075 g, 26.87 mmol) at 0° C., and themixture was stirred at 0° C. for 4 hr. To the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givemethyl2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate(2.470 g, 5.26 mmol, 43.1%) as an orange oil.

(Step 6)

To a solution of methyl2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate(2.17 g, 4.62 mmol) in THF (30 mL) was added 1M DIBAL-H/THF solution(13.87 mL, 13.87 mmol) at 0° C., and the mixture was stirred at 0° C.for 5 hr. 1M DIBAL-H/THF solution (1.0 mL, 1.0 mmol) was added againthereto at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. Tothe reaction mixture were added 1N hydrochloric acid and water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→50% ethylacetate/hexane), and then silica gel column chromatography (NH, solventgradient; 3→50% ethyl acetate/hexane) to give2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(1.310 g, 2.97 mmol, 64.2%) as a colorless oil.

(Step 7)

To a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(1.31 g, 2.97 mmol) and iodomethane (0.278 mL, 4.45 mmol) in DMF (10 mL)was added sodium hydride (60%, oil, 0.154 g, 3.86 mmol) at 0° C., andthe mixture was stirred at 0° C. for 4 hr. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→40% ethyl acetate/hexane) to give3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline(1.000 g, 2.195 mmol, 74.0%) a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ1.37-1.42 (6H, m), 3.33 (3H, s), 3.50 (2H, s),3.80 (6H, s), 4.46 (4H, s), 6.08-6.24 (2H, m), 6.86 (4H, d, J=8.3 Hz),7.11 (4H, d, J=8.7 Hz).

(Step 8)

A solution of3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline(1 g, 2.20 mmol) in TFA (10 mL) was stirred at room temperature for 1hr. The reaction mixture was concentrated under reduced pressure, and tothe obtained residue was added ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→50% ethylacetate/hexane) to give3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (0.470 g, 2.184mmol, 99%) as a pale-yellow oil.

¹H NMR (300 MHz, CDCl₃): δ1.40 (6H, t, J=2.5 Hz), 3.32 (3H, s), 3.50(2H, s), 3.69 (2H,brs), 6.07-6.16 (2H, m).

(Step 9) To a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (671 mg, 2.18 mmol),3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (470 mg, 2.18mmol), DIEA (1.907 mL, 10.92 mmol) and DMAP (267 mg, 2.18 mmol) in ethylacetate (30 mL) was added T3P (3.85 mL, 6.55 mmol) at room temperature,and the mixture was stirred overnight at 60° C. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→60% ethyl acetate/hexane), and then silica gel columnchromatography (NH, solvent gradient; 5→60% ethyl acetate/hexane), andthe precipitate was washed with ethyl acetate/hexane to give tert-butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(440 mg, 0.872 mmol, 39.9%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ1.42 (6H, t, J=2.3 Hz), 1.51 (9H, s),2.72-2.99 (2H, m), 3.30 (3H, s), 3.46-3.75 (4H, m), 3.80 (3H, s), 5.57(1H, brs), 6.73 (1H, s), 6.81 (1H,dd,J=8.5,2.8 Hz), 6.94-7.11 (2H, m),7.10-7.20 (1H, m), 8.93 (1H, brs).

(Step 10)

tert-Butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(440 mg) was subjected to optical resolution by chiral columnchromatography. The fraction having a shorter retention time wasconcentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(200 mg, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD(NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 11)

To a solution of tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(200 mg, 0.40 mmol) in ethyl acetate (3 mL) was added 4M hydrogenchloride/ethyl acetate (4 mL) at room temperature, and the mixture wasstirred overnight. The reaction mixture was concentrated under reducedpressure to give(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (175 mg, 0.397 mmol, 100%) as white crystals.

(Step 12)

HATU (114 mg, 0.30 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (120 mg, 0.27 mmol),cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (61.2 mg,0.29 mmol) and DIEA (0.107 mL, 0.60 mmol) in DMF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give tert-butyl2-(cis-3-((R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(120 mg, 0.200 mmol, 73.4%) as a colorless oil.

MS(API): Calculated 600.7, Found 599.2 (M-H).

(Step 13)

Cooled TFA (4 mL) was added to tert-butyl2-(cis-3-((R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate(120 mg, 0.20 mmol) at 0° C., and the mixture was stirred for 45 min.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (106 mg, 0.195 mmol, 97%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.35 (6H, s), 1.71-1.92 (3H, m), 2.20-2.36(5H, m), 2.73-2.83 (1H, m), 2.98-3.12 (1H, m), 3.19 (3H, s), 3.40-3.53(3H, m), 3.69-3.77 (3H, m), 3.83-4.02 (1H, m), 5.41-5.62 (1H,m),6.72-6.91 (2H, m), 7.07-7.27 (2H, m), 7.34-7.56 (1H, m), 10.51-10.77(1H, m), 11.99 (1H, brs).

The compounds described in Examples 1 to 35 are below (Table 1-1-Table1-7).

TABLE 1-1 Ex. IUPAC NAME Structure SALT MS 1trans-2-(((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclopropanecarboxylicacid (a mixture of two diastereomers)

503.2 (M + H) 2 trans-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclopropanecarboxylicacid (single stereoisomer, shorter retention time)

503.1 (M + H) 3 trans-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclopropanecarboxylicacid (single stereoisomer, longer retention time)

501.2 (M − H) 4 (3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

531.2 (M + H) 5 cis-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutanecarboxylicacid

515.1 (M − H)

TABLE 1-2 Ex. IUPAC NAME Structure SALT MS 6((1R,2S)-2-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)acetic acid

496.1 (M + H) 7 ((1S,2R)-2-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclopropyl)acetic acid

496.2 (M + H) 8 cis-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutanecarboxylicacid

531.2 (M + H) 9 trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutanecarboxylicacid

531.2 (M + H) 10 cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutanecarboxylic acid

496.0 (M + H)

TABLE 1-3 Ex. IUPAC NAME Structure SALT MS 11trans-3-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylic acid

496.1 (M + H) 12 trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutanecarboxylicacid

517.2 (M + H) 13 ((1R,2S)-2-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)acetic acid

518.1 (M + H) 14 ((1S,2R)-2-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopropyl)acetic acid

518.2 (M + H) 15 (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetic acid

510.2 (M + H)

TABLE 1-4 Ex. IUPAC NAME Structure SALT MS 16(cis-3-(((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbarnoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetic acid

523.3 (M + H) 17 (cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2- yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

559.2 (M + H) 18 (cis-3-(((1R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5- difluorophenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

573.3 (M + H) 19 (cis-3-(((1R)-1-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

523.1 (M + H) 20 (trans-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetic acid

510.3 (M + H)

TABLE 1-5 Ex. IUPAC NAME Structure SALT MS 21(cis-3-(((6R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7(2H)-yl)carbonyl)cyclobutyl)acetic acid

521.3 (M + H) 22 (cis-3-(((7R)-7-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2,3,9,10-tetrahydro[1,4]dioxino[2,3- f]isoquinolin-8(7H)-yl)carbonyl)cyclobutyl)acetic acid

537.2 (M + H) 23 (cis-3-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetic acid

532.1 (M + H) 24 (trans-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

523.3 (M + H) 25 (cis-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

531.2 (M + H)

TABLE 1-6 Ex. IUPAC NAME Structure SALT MS 26(trans-3-(((1R)-1-((3,5-difluoro-4-(1- methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetic acid

559.3 (M + H) 27 (trans-3-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

531.2 (M + H) 28 (trans-3-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetic acid

532.1 (M + H) 29 ((1R,2S)-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclopropyl)aceticacid

517.2 (M + H) 30 ((1S,2R)-2-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclopropyl)aceticacid

517.2 (M + H)

TABLE 1-7 Ex. IUPAC NAME Structure SALT MS 31cis-3-(((5R)-5-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylic acid

518.1 (M + H) 32 cis-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutanecarboxylicacid

499.2 (M + H) 33 (cis-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

513.1 (M + H) 34 (trans-3-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetic acid

513.2 (M + H) 35 (cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2- yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H, yl)carbonyl)cyclobutyl)acetic acid

545.2 (M + H)

The compounds described in Examples 7, 16, 21, 22 and 26 weresynthesized in the same manner as in the reaction and purificationdescribed in the above-mentioned Examples.

Example 36 benzylcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylate(Step 1)

To a solution of cis-cyclobutane-1,3-dicarboxylic acid (4.00 g, 27.75mmol), benzyl alcohol (2.87 mL, 27.75 mmol) and DMAP (0.339 g, 2.78mmol) in DMF (80 mL) was added WSC (5.59 mL, 30.53 mmol) at roomtemperature, and the mixture was stirred overnight. The reaction mixturewas poured into water, and the pH of the mixture was adjusted to 2 to 3with 1N hydrochloric acid. The mixture was extracted with ethyl acetate,and the organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give crude cis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid(5.93 g, 25.3 mmol, 91%) as a colorless oil. This compound was used forthe next step without purification.

(Step 2)

HATU (9.88 g, 25.99 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(8.0 g, 21.65 mmol), DIEA (7.40 mL, 43.31 mmol) and the crudecis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (6.59 g, 28.15mmol) in DMF (150 mL) at room temperature, and the mixture was stirredat room temperature for 5 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→50%ethyl acetate/hexane). The obtained solid was recrystallized from ethylacetate/hexane to give the title compound (5.50 g, 9.39 mmol, 43.4%) aswhite crystals.

[α]_(D) ²⁵ +109.5 (c 0.2500, MeOH)

¹H NMR (300 MHz, CDCl₃): δ1.34 (6H, s), 1.91 (2H, t, J=7.4 Hz),2.45-2.62 (2H, m), 2.63-2.78 (2H, m), 2.86 (2H, t, J=7.4 Hz), 2.91-3.03(2H, m), 3.11-3.26 (1H, m), 3.25-3.41 (1H, m), 3.57-3.70 (1H, m),3.76-3.87 (1H, m), 3.92 (3H, s), 5.14 (2H, s), 5.98 (1H, s), 6.66 (1H,d, J=8.7 Hz), 7.04-7.10 (1H, m), 7.12-7.20 (1H, m), 7.35 (5H, s), 7.41(1H, d, J=8.3 Hz), 9.00 (1H, s)

Example 38 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate

4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (77 μL, 0.71 mmol) was addedto a mixture of2-(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-tetrahydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (300 mg, 0.59 mmol) and potassium carbonate (98 mg, 0.71 mmol) inDMF (5 mL) at room temperature, and the mixture was stirred at roomtemperature for 4 hr. To the reaction mixture was added water (60 mL),and the mixture was extracted with ethyl acetate (×3). The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 50→71% ethylacetate/hexane) to give the title compound (258.0 mg, 0.415 mmol, 70.5%)as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.32 (6H, s), 1.89 (2H, t, J=7.4 Hz), 2.11(2H,d,J=10.6 Hz), 2.17 (3H, s), 2.42-2.53 (4H, m), 2.62-2.77 (1H, m),2.85 (2H, t, J=7.4 Hz), 2.91-3.03 (2H, m), 3.31 (1H,quin,J=8.9 Hz),3.61-3.72 (1H, m), 3.84 (1H,dt), 3.91 (3H, s), 4.82 (2H, s), 5.96 (1H,s), 6.64 (1H,d,J=8.7 Hz) 7.05 (1H, s), 7.10 (1H, d, J=11.7 Hz), 7.43(1H, d, J=8.7 Hz), 9.09 (1H, s)

Example 39 ethyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate

Iodoethane (57 μL, 0.71 mmol) was added to a mixture of2-(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-tetrahydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (300 mg, 0.59 mmol) and potassium carbonate (98 mg, 0.71 mmol) inDMF (5 mL) at room temperature, and the mixture was stirred at roomtemperature for 3.5 hr. To the reaction mixture was added water (60 mL),and the mixture was extracted with ethyl acetate (×3). The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 25→46% ethylacetate/hexane) to give the title compound (256.8 mg, 0.478 mmol, 81%)as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.24 (3H, t, J=7.2 Hz), 1.32 (6H, s), 1.89(2H,t,J=7.4 Hz), 2.04-2.17 (2H, m), 2.40-2.54 (4H, m), 2.62-2.78 (1H,m), 2.84 (2H, t, J=7.4 Hz), 2.89-3.05 (2H, m), 3.31 (1H,quin,J=8.9 Hz),3.64-3.75 (1H, m), 3.81-3.89 (1H, m), 3.91 (3H, s), 4.11 (2H,q,J=7.2Hz), 5.98 (1H, s), 6.64 (1H, d, J=8.7 Hz), 7.02 (1H, s), 7.10 (1H, d,J=11.7 Hz), 7.47 (1H, d, J=8.7 Hz), 9.22 (1H, s)

Example 40-A monopotassium(cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetateacetonitrile solvate

To a mixture of(cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)aceticacid (580 mg, 1.11 mmol) in acetonitrile (40 mL) was added 0.1N aqueouspotassium hydroxide solution (11.10 mL, 1.11 mmol) at room temperature,and the solvent was evaporated under reduced pressure. To the obtainedresidue was added acetonitrile (40 mL), and the mixture was stirred atroom temperature for 14 hr. The precipitate was collected by filtration,and washed with acetonitrile to give the title compound (586.6 mg, 1.046mmol, 94%) as white crystals.

¹H NMR (300 MHz, CD₃OD): δ33 (6H, s), 2.03 (4H, s), 2.18-2.34 (2H, m),2.34-2.52 (2H, m), 2.56-2.74 (1H, m), 2.79-2.94 (3H, m), 3.10-3.23 (1H,m), 3.36 (4H, s), 3.54-3.68 (1H,m), 3.92-4.07 (1H, m), 4.43 (2H, s),5.51-5.75 (1H, m), 7.06-7.16 (2H, m), 7.18-7.28 (2H, m), 7.45 (1H, d,J=8.3 Hz)

[α]_(D) ²⁵ +39.7 (c 0.2515, MeOH)

The crystallinity by powder X-RAY diffraction was 64.3%.

The peaks by powder X-RAY diffraction were below.

TABLE 2 peak search- intensity relative No. 2θ d value set width (cps)intensity 1 5.080 17.3812 0.2118 635 100 2 7.200 12.2675 0.2353 275 44 313.900 6.3658 0.2118 354 56 4 15.340 5.7713 0.2353 395 63 5 16.1605.4803 0.2118 182 29 6 17.300 5.1216 0.3294 202 32 7 18.020 4.91860.2118 407 65 8 18.440 4.8075 0.2118 148 24 9 18.840 4.7063 0.3294 13321 10 19.540 4.5392 0.2824 155 25 11 20.140 4.4054 0.2353 304 48 1221.160 4.1952 0.1882 159 26 13 22.080 4.0225 0.3529 160 26 14 22.6403.9242 0.2353 321 51 15 22.960 3.8703 0.1647 246 39 16 24.360 3.65090.3529 198 32 17 25.720 3.4609 0.2118 126 20 18 26.520 3.3582 0.3059 12320 19 26.980 3.3020 0.2588 155 25 20 28.940 3.0827 0.2353 133 21 2130.340 2.9436 0.2353 135 22

Example 40-B monopotassium(cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetatemethyl ethyl ketone solvate

Monopotassium(cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetateacetonitrile solvate (30 mg, 0.05 mmol) was dissolved in MEK (2 mL), andthe solution was stood to give the title compound (21.2 mg, 0.038 mmol,71%) as white crystals.

¹H NMR (300 MHz, CD₃OD): δ1.36 (s, 6H), 1.87-2.11 (m, 4H), 2.20-2.39 (m,2H), 2.38-2.58 (m, 2H), 2.60-2.77 (m, 1H), 2.91 (t, J=7.36 Hz, 3H),3.12-3.27 (m, 1H), 3.36-3.50 (m, 4H), 3.55-3.77 (m, 1H), 3.93-4.11 (m,1H), 4.46 (s, 2H), 5.75 (s, 1H), 7.12 (s, 2H), 7.23 (s, 2H), 7.48 (d,J=8.31 Hz,1H) (The exchangeable 1H was not observed. The signals of MEKwere omitted).

The crystallinity by powder X-RAY diffraction was 62.5%.

The peaks by powder X-RAY diffraction were below.

TABLE 3 peak search- intensity relative No. 2θ d value set width (cps)intensity 1 4.940 17.8735 0.2118 1885 100 2 6.720 13.1426 0.2118 421 233 7.420 11.9042 0.2353 488 26 4 10.900 8.1102 0.2118 284 16 5 14.8805.9487 0.2118 623 34 6 15.360 5.7638 0.2118 1335 71 7 15.680 5.64690.1647 309 17 8 17.260 5.1334 0.2118 506 27 9 17.580 5.0407 0.2118 25314 10 18.060 4.9078 0.1882 232 13 11 18.440 4.8075 0.1882 301 16 1219.000 4.6670 0.2118 219 12 13 20.440 4.3414 0.2588 285 16 14 20.7004.2874 0.1647 315 17 15 21.000 4.2268 0.1882 239 13 16 21.560 4.11830.3529 369 20 17 22.020 4.0333 0.4235 422 23 18 22.480 3.9518 0.2118 27915 19 23.240 3.8243 0.2118 695 37 20 23.700 3.7511 0.1882 310 17 2127.340 3.2594 0.2118 258 14 22 29.740 3.0016 0.2118 215 12

Example 42-A(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid monosulfate hemihydrate

0.126M Sulfuric acid/THF (13.24 mL, 1.67 mmol) solution was added to asolution of(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydrol,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (850 mg, 1.67 mmol) in THF (20 mL) at room temperature. The mixturewas concentrated under reduced pressure to dryness, and the solid wascollected by filtration with ethyl acetate (20 mL) to give(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid monosulfate (980.1 mg, 1.613 mmol, 97%) as a white solid.

The obtained(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid monosulfate (300 mg, 0.49 mmol) was dissolved in MEK (600 μL) whilewarming at water-bath (60° C.). After changing to an oil, the oil wasstood overnight at room temperature. The precipitated white crystalswere stood at refrigerator for several weeks to give the title compound.

The crystallinity by powder X-RAY diffraction was 49.1%.

The peaks by powder X-RAY diffraction were below.

TABLE 4 peak search- intensity relative No. 2θ d value set width (cps)intensity 1 4.040 21.8530 0.4471 432 41 2 8.620 10.2495 0.2353 435 41 311.060 7.9932 0.2353 421 40 4 13.820 6.4025 0.1882 292 28 5 16.6005.3360 0.2588 558 53 6 17.240 5.1393 0.2118 1063 100 7 18.240 4.85970.4000 475 45 8 18.900 4.6915 0.1882 262 25 9 19.340 4.5857 0.2588 40739 10 19.880 4.4624 0.2118 372 35 11 20.380 4.3540 0.1882 475 45 1221.100 4.2070 0.2588 587 56 13 21.860 4.0625 0.2588 483 46 14 22.2004.0010 0.2118 848 80 15 22.540 3.9414 0.2118 597 57 16 23.560 3.77300.2118 476 45 17 23.960 3.7109 0.2118 433 41 18 24.440 3.6391 0.1882 31030 19 25.280 3.5201 0.2118 332 32 20 25.720 3.4609 0.1647 535 51 2125.940 3.4320 0.1882 778 74 22 26.340 3.3808 0.4000 298 29 23 28.8803.0890 0.2118 344 33

Example 42-B(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid monosulfate monohydrate

To a solution of(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (5 g, 9.81 mmol) in MEK (50.0 mL) was added a mixture of sulfuricacid (0.575 mL, 10.79 mmol) and acetic acid (2.292 mL, 40.03 mmol). Tothe mixture were added acetonitrile (25.00 mL) and the seed crystalsobtained in Example 42-A, and the mixture was stirred at 60° C. for 1hr. Then, cyclopropylmethyl ether (50.0 mL) was added thereto, and themixture was stirred at 60° C. for 2 hr, and then at room temperature for16 hr. The mixture was cooled in ice bath, and the precipitate wascollected by filtration, and washed with MEK (30 mL). The crystals weredried to give a pale-brown solid (4.82 g, 7.93 mmol, 81%). To theobtained solid was added MEK (96 mL), and the mixture was suspended at60° C. for 1 hr, and cooled, and the precipitate was collected byfiltration, and washed with MEK (20 mL). The crystals were dried at 50°C. under reduced pressure to give the title compound (4.30 g, 6.87 mmol,70.0%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (6H, s), 1.75-1.95 (4H, m), 2.24-2.40(4H, m), 2.43-2.49 (1H, m), 2.53-2.59 (1H, m), 2.77-2.91 (3H, m), 2.98(1H, dt, J=16.7, 4.8 Hz), 3.37 (1H, quin, J=8.8 Hz), 3.77 (1H, dt,J=13.0, 5.4 Hz), 3.83 (3H, s), 3.96 (1H, ddd, J=12.9, 8.6, 4.5 Hz), 5.72(1H, s), 6.73 (1H, d, J=8.7 Hz), 7.19 (1H, s), 7.23 (1H, d, J=12.5 Hz),7.79 (1H, d, J=8.7 Hz), 8.43 (4H, brs), 10.51 (1H, s).

[α]_(D) ²⁵ +86.2 (c 0.2520, MeOH)

The crystallinity by powder X-RAY diffraction was 57.7%.

The peaks by powder X-RAY diffraction were below.

TABLE 5 peak search- intensity relative No 2θ d value set width (cps)intensity 1 4.060 21.7454 0.2118 887 84 2 8.620 10.2495 0.2118 571 54 38.980 9.8394 0.1882 368 35 4 11.000 8.0367 0.2353 463 44 5 13.780 6.42100.2118 332 32 6 15.500 5.7121 0.1647 267 26 7 15.800 5.6043 0.3059 27026 8 16.600 5.3360 0.2118 731 70 9 17.200 5.1512 0.2118 1059 100 1018.060 4.9078 0.2353 435 42 11 18.300 4.8439 0.2353 399 38 12 19.2404.6093 0.2588 348 33 13 19.760 4.4892 0.2588 326 31 14 20.340 4.36250.2118 352 34 15 21.060 4.2149 0.2118 594 57 16 21.440 4.1411 0.1647 32331 17 21.820 4.0698 0.2353 614 58 18 22.160 4.0081 0.1882 780 74 1922.440 3.9588 0.1647 514 49 20 23.660 3.7573 0.2353 531 51 21 24.4003.6450 0.1882 314 30 22 25.240 3.5256 0.2118 314 30 23 25.720 3.46090.2118 567 54 24 28.900 3.0869 0.2824 314 30

Example 43cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid monosulfate

0.126M Sulfuric acid/THF (8.01 mL, 1.01 mmol) solution was added to asolution ofcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid (500 mg, 1.01 mmol) in THF (10 mL) at room temperature. The mixturewas concentrated under reduced pressure to dryness, and the solid wascollected by filtration with ethyl acetate (10 mL) to give the titlecompound (548.3 mg, 0.924 mmol, 92%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.25-1.32 (6H, m), 1.87 (2H, t, J=7.4 Hz),2.20-2.44 (4H, m), 2.76-2.91 (3H, m), 2.92-3.09 (2H, m), 3.35-3.51 (1H,m), 3.69-3.80 (1H, m), 3.82 (3H, s), 3.90-4.02 (1H, m), 5.46-5.79 (1H,m), 6.72 (1H, d, J=8.3 Hz), 7.13-7.31 (2H, m), 7.69-7.86 (1H, m),10.39-10.62 (1H, m), 12.13 (1H, brs) (The exchangeable 2H was notobserved).

Example 44 (5-methyl-2-oxo-1,3-dioxol-4-yl)methylcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylate

4-Chloromethyl-5-methyl-1,3-dioxolan-2-one (0.026 mL, 0.24 mmol) wasadded to a mixture ofcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid (100 mg, 0.20 mmol) and potassium carbonate (33.5 mg, 0.24 mmol) inDMF (2.0 mL) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 20→50% ethylacetate/hexane) to give the title compound (58.2 mg, 0.096 mmol, 47.5%)as a white amorphous solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (6H, s), 1.87 (2H, t, J=7.2 Hz), 2.14(3H, s), 2.24-2.47 (4H, m), 2.77-2.91 (3H, m), 2.92-3.04 (1H, m),3.08-3.25 (1H, m), 3.36-3.66 (1H, m), 3.69-3.80 (1H, m), 3.82 (3H, s),3.88-4.02 (1H, m), 4.94 (2H, s), 5.49-5.73 (1H, m), 6.72 (1H, d, J=8.3Hz), 7.12-7.29 (2H, m), 7.72-7.84 (1H, m), 10.38-10.59 (1H, m)

Example 45 methyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate

(Diazomethyl)trimethylsilane (0.6M hexane solution) (0.392 mL, 0.24mmol) was added to a mixture of(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (1 mL) at 5° C., and themixture was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→50% ethyl acetate/hexane) to give the title compound (50 mg,0.095 mmol, 81%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.31 (s, 6H), 1.83-1.93 (m, 2H), 2.05-2.18 (m,2H), 2.36-2.57 (m, 4H), 2.61-3.09 (m, 5H), 3.24-3.42 (m, 1H), 3.65 (s,3H), 3.71-3.87 (m, 2H), 3.91 (s, 3H), 5.99 (s,1H), 6.62 (d, J=8.69 Hz,1H), 6.99 (s,1H), 7.04-7.13 (m, 1H), 7.54 (d, J=8.31 Hz, 1H), 9.40 (s,1H)

Example 46 methylcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylate

(Diazomethyl)trimethylsilane (0.6M hexane solution) (0.404 mL, 0.24mmol) was added to a mixture ofcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (1 mL) at 5° C., and themixture was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→50% ethyl acetate/hexane) to give the title compound (50 mg,0.098 mmol, 81%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.31 (s, 6H), 1.82-1.94 (m, 2H), 2.44-2.75 (m,4H), 2.77-3.23 (m, 5H), 3.27-3.43 (m, 1H), 3.66 (brs, 1H), 3.71-3.85 (m,2H), 3.91 (s, 3H), 5.99 (s, 1H), 6.66 (d, J=8.69 Hz, 1H), 6.97-7.05 (m,1H), 7.06-7.17 (m, 1H), 7.51 (d, J=8.31 Hz, 1H), 9.24 (s, 1H)

Example 47 benzyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate

Benzyl bromide (84 μL, 0.71 mmol) was added to a mixture of(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)aceticacid (300 mg, 0.59 mmol) and potassium carbonate (98 mg, 0.71 mmol) inDMF (5 mL) at room temperature, and the mixture was stirred at roomtemperature for 2.5 hr. To the reaction mixture was added water (60 mL),and the mixture was extracted with ethyl acetate (×3). The organic layerwas washed with water and brine, and dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→41% ethyl acetate/hexane) to give the title compound (282.3 mg, 0.471mmol, 80%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ1.31 (6H, s), 1.88 (2H, t, J=7.4 Hz),2.04-2.17 (2H, m), 2.41-2.53 (4H, m), 2.63-2.79 (1H, m), 2.83 (2H, t,J=7.2 Hz), 2.87-3.04 (2H, m), 3.30 (1H,quin,J=8.9 Hz), 3.69 (1H, ddd),3.84 (1H,dt), 3.91 (3H, s), 5.09 (2H, s), 5.97 (1H, s), 6.63 (1H, d,J=8.7 Hz), 7.01 (1H, s), 7.10 (1H,d,J=11.7 Hz), 7.28-7.38 (5H, m), 7.46(1H, d, J=8.7 Hz), 9.22 (1H, s)

The compounds described in Examples 36 to 48 are below (Table 6-1 toTable 6-3).

TABLE 6-1 SALT Ex. IUPAC NAME Structure ADDITIVE MS 36 benzylcis-3-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutane carboxylate

584.3 (M − H) 37 tert-butyl (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate

566.2 (M + H) 38 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetate

622.1 (M + H) 39 ethyl (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetate

536.2 (M − H) 40A monopotassium (cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate acetonitrile solvate

K 521.2 (M − H) 40B monopotassium (cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate methyl ethyl ketone solvate

K Not tested

TABLE 6-2 SALT Ex. IUPAC NAME Structure ADDITIVE MS 41 tert-butyl(cis-3-(((1R)-1-((7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate

579.2 (M + H) 42A (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetic acid monosulfatehemihydrate

H₂SO₄ 1/2H₂O 510.3 (M + H) 42B (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetic acid monosulfatemonohydrate

H₂SO₄ H₂O 510.3 (M + H) 43 cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutanecarboxylic acid monosulfate

H₂SO₄ 494.2 (M − H) 44 (5-methyl-2-oxo-1,3-dioxol-4-yl)methylcis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutanecarboxylate

608.1 (M + H) 45 methyl (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H- yl)carbonyl)cyclobutyl) acetate

524.2 (M + H)

TABLE 6-3 SALT Ex. IUPAC NAME Structure ADDITIVE MS 46 methylcis-3-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylate

508.2 (M − H) 47 benzyl (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)carbonyl)cyclobutyl)acetate

600.2 (M + H) 48 methyl (cis-3-(((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)cyclobutyl)acetate

537.3 (M + H)

The compounds described in Examples 37, 41 and 48 were synthesized inthe same manner as in the reaction and purification described in theabove-mentioned Examples.

Experimental Example 1 RORγt Binding Test Using Fluorescent-LabeledSynthetic Ligand

The fluorescent-labeled synthetic ligand was synthesized as follows.

(Step 1)

A solution of (4-(methoxymethyl)phenyl)boronic acid (999 mg, 6.02 mmol),glyoxylic acid monohydrate (554 mg, 6.02 mmol) and diallylamine (0.741mL, 6.02 mmol) in acetonitrile (12 mL) was stirred at 60° C. for 5 hr.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent; ethyl acetate), and crystallized from ethyl acetate/hexane togive 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (200 mg,0.726 mmol, 12.07%) as crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 3.04-3.46 (7H, m), 4.39 (2H, s), 4.43 (1H,s), 5.04-5.23 (4H, m), 5.78 (2H,ddt,J=16.9,10.5,6.3 (4H,m)

(Step 2)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (5 g, 24.84mmol), 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (8.21 g,29.81 mmol), DMAP (3.34 g, 27.32 mmol) and DIEA (21.69 mL, 124.20 mmol)in ethyl acetate (150 mL) was added T3P (29.2 mL, 49.68 mmol), and themixture was stirred at 80° C. for 2 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 0→4.10% ethyl acetate/hexane) to give2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(6.79 g, 14.81 mmol, 59.6%) as a pale-yellow oil. This compound was usedfor the next step without further purification.

(Step 3)

To a solution of2-(diallylamino)-N-(3,5-difluoro-4-(trimethyisilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(6.79 g, 14.81 mmol) and 1,3-dimethylbarbituric acid (4.85 g, 31.09mmol) in THF (120 mL) was added Pd(PPh₃)₄ (0.684 g, 0.59 mmol), and themixture was stirred overnight at room temperature under argonatmosphere. The reaction solution was concentrated, and the obtainedresidue was purified by silica gel column chromatography (NH, solventgradient; 50→100% ethyl acetate/hexane) to give crude2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(4.00 g) as a colorless oil.

(Step 4)

To a solution of the crude2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(9.07 mg, 0.02 mmol) in DMF (0.5 mL) was added1-((5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)pentanoyl)oxy)pyrrolidine-2,5-dione(BODIPY (registered trademark) FL-05 succinimidyl ester) (5.0 mg, 0.01mmol) at room temperature, and the mixture was stirred at roomtemperature for 3 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent; ethyl acetate/hexane), andthen preparative HPLC (C18, mobile phase: water/acetonitrile (containing0.1% TFA)) to give5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)-N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pentanamide(3.8 mg, 5.58 μmol, 46.6%) as an orange solid, which is afluorescent-labeled synthetic ligand.

¹H NMR (300 MHz, CDCl₃): δ0.31 (9H, t, J=1.3 Hz), 1.71-1.87 (4H, m),2.25 (3H, s), 2.32-2.42 (2H, m), 2.53 (3H, s), 2.91-3.03 (2H, m), 3.35(3H, s), 4.40 (2H, s), 5.71 (1H, d, J=7.2 Hz), 6.09 (1H, s), 6.23 (1H,d, J=4.2 Hz), 6.80-6.90 (2H, m), 6.90-6.99 (2H, m), 7.06 (1H, s),7.23-7.31 (2H, m), 7.33-7.42 (2H, m), 8.63 (1H, s).

MS(API): Calculated 680.6, Found 679.4 (M-H).

The binding activity of the test compound to RORγt was measured by atime resolved fluorescence resonance energy transfer method (TR-FRET)utilizing histidine-tagged RORγt, fluorescent-labeled synthetic ligandand terbium-labeled anti-histidine tag antibody (Invitrogen). First, atest compound diluted with an assay buffer (20 mM Tris-HCl (pH 7.5), 100mM NaCl, 1 mM DTT, 0.1% BSA) was added to a 384 well plate by 3 μL.Then, RORγt diluted with an assay buffer to 240 nM was added by 3 μL,after which fluorescent-labeled synthetic ligand diluted with the assaybuffer to 12 μM was added by 3 μL, and the mixture was stood at roomtemperature for 20 min. Thereafter, a terbium-labeled anti-histidine tagantibody diluted with the assay buffer to 8 nM was added by 3 μL. Themixture was stood at room temperature for 20 min, and fluorescenceintensity (excitation wavelength 320 nm, fluorescence wavelength 520 nm,delay time 100 microseconds) was measured by Envision (PerkinElmer).

The results (binding inhibitory rate of fluorescent-labeled syntheticligand to RORγt at test compound 1 μM) measured by the above-mentionedmethod are shown in Table 7.

Experimental Example 2 Cofactor Recruitment Test

Cofactor recruitment test was performed by Alpha Screen (HistidineDetection Kit, PerkinElmer) method. First, a test compound was dilutedwith an assay buffer (50 mM Tris-HCl (pH 7.5), 50 mM KCl, 1 mM DTT, 0.1%BSA) and added to a 384 well plate by 5 μL. Then, RORγt diluted with anassay buffer to 125 nM was added by 10 μL each, after which solutions of25 nM biotinylated SRC-1 peptide (biotin-CLTARHKILHRLLQEGSPSD), 12.5μg/mL acceptor beads and 12.5 μg/mL donor beads prepared with the assaybuffer were added by 10 μL each. The mixture was stood in a dark placefor 1 hr, and the signal value was measured by Envision (PerkinElmer).

The results (signal value inhibitory rate at test compound 1 μM)measured by the above-mentioned method are shown in Table 7.

Experimental Example 3 Jurkat Reporter Test

The Jurkat cells used for the reporter test were cultured in a culturemedium (RPMI (Invitrogen), 10% FCS (AusGeneX), 100 U/mL penicillin, 100μg/mL streptomycin). On the day of the test, 4×10⁷ cells were recoveredby a centrifugal operation (1000 rpm, 5 min.) and suspended in PBS(phosphate buffered saline) (Invitrogen). Thereafter, the cells wererecovered again by a centrifugal operation, and suspended in 2 mL of Rbuffer (NEON transfection kit, Invitrogen). Then, a reporter vector (53μg) wherein a human IL-17 ROR response element was inserted into theupstream of luciferase of pGL 4.28 (Promega), and a vector (27 μg)wherein RORγt sequence was inserted into the downstream of CMV promoterwere added to the cell suspension. Gene transfer was performed byElectroporation apparatus (NEON, Invitrogen) under the conditions ofpulse voltage 1350 V, interval 10 milliseconds, number of times 3. Thecells after gene transfer were suspended in 40 mL of a reaction medium(RPMI, 10% Lipid reduced FCS (HyClone), 10 mM HEPES (pH 7.5), 100 U/mLpenicillin, 100 μg/mL streptomycin, 5 μM lovastatin), and plated in a 96well plate by 90 μL. A test compound diluted with the reaction mediumwas added by 10 μL, and the cells were cultured overnight in anincubator. Bright-Glo (Promega) was added by 100 μL, and the mixture wasstirred at room temperature for 10 min, and the luminescence level wasmeasured by Envision (PerkinElmer).

The results (luminescence level inhibitory rate at test compound 3 μM)measured by the above-mentioned method are shown in Table 7.

TABLE 7 Experimental Example 1 Experimental binding inhibitoryExperimental Example 3 rate of fluorescent- Example 2 luminescencelabeled synthetic signal value level inhibitory ligand to RORγt atinhibitory rate at rate at test Ex. test compound test compound compoundNo. 1 μM (%) 1 μM (%) 3 μM (%)  3 102% 84%  97%  4 102% 94% 100%  5 102%93% 100%  6 102% 54%  97%  8 102% 90% 100%  9 102% 88%  99% 10 102% 62% 98% 11 102% 58%  98% 12 102% 91%  99% 13 102% 83% 104% 14 101% 86% 100%15 102% 60%  99% 17 101% 85%  99% 18 101% 70%  97% 19 101% 82%  99% 20101% 54%  98% 23 102% 87% 101% 24 101% 80% 101% 25 102% 93% 101% 27 102%91% 103% 28 102% 87% 101% 29 102% 91% 102% 30 101% 90% 100% 31 102% 86%102% 32 102% 91% 101% 33 102% 92% 102% 34 102% 88% 100% 35 102% 83%  99%36 102% 72% 102% 38 102% 61% 102% 39 101% 63% 103% 40-A 102% 87% 104% 43102% 62% 102% 44 102% 61% 102% 45 101% 66% 101% 46 102% 69% 102%

Experimental Example 4 Effect on IL-17 Production in Human Blood

The inhibitory effect of the test compound on IL-17 production in humanblood was evaluated as follows. First, 150 μL of peripheral bloodcollected from healthy individuals using heparinized vacuum bloodcollection tubes was dispensed into each well of a 96-well plate(Corning), and 45 μL, of RPMI 1640 medium (Gibco) containing 10% fetalbovine serum (FBS, Hyclone) and 30 μL of the test compound diluted withthe medium were added to each well. The plate was then cultured for 30min at 37° C. The cells were subsequently stimulated by adding 30 μL of100 ng/mL human IL-23 (R&D) and 45 μL of Dynabeads Human (Invitrogen) toeach well and culturing the plate for 3 days at 37° C. In wells withoutstimulation, 75 μL of RPMI 1640 medium containing 10% FBS was addedinstead of the IL-23 and Dynabeads solution. After culturing for 3 days,the culture supernatant was collected, and the amount of IL-17 in thesupernatant was measured using an IL-17 ELISA kit (R&D).

The results (percent inhibition of IL-17 production with 10 μM of thetest compound) measured by the above-mentioned method are shown in Table8.

TABLE 8 Example percent inhibition number at 10 μM 4 88.3% 5 88.6% 686.6% 8 82.9% 9 93.5% 10 89.7% 15 94.0% 18 80.0% 19 94.1% 23 85.9% 2492.7% 28 89.1% 29 74.9% 31 89.8% 33 78.5%

The results above showed that the example compounds inhibited IL-17production in human blood.

Experimental Example 5 Effect on IL-23-Induced Cytokine Expression inMice

A mouse IL-23 solution (500 ng/10 μL, prepared by Takeda PharmaceuticalCompany Limited) or PBS (10 μL, negative control group) was administeredintradermally in the ear of Balb/c mice (Charles River Japan, male, 7weeks old). Twenty-four hr after administration, the ear was resectedunder isoflurane anesthesia. The test compound was suspended in 0.5%methylcellulose and administered orally 30 min before and 8 hr afterIL-23 administration.

RNA extraction from the ear tissue and quantitative PCR were performedas follows. Specifically, ear tissue 5 mm in diameter was punched froman area of the resected ear centering on the IL-23 injection site, andthe tissue was immersed in RNAlater (QIAGEN) for at least 18 hr. TheRNAlater-treated ear tissue was homogenized in 350 μL of RLT buffer(RNeasy mini kit, QIAGEN) and treated (55° C., 10 min) with Proteinase K(QIAGEN). Total RNA was then extracted according to the RNeasy mini kitprotocol. The RNA thus obtained was then reverse transcribed into cDNAusing the High-Capacity RNA-to-cDNA kit (Applied Biosystems), and theamount of each gene expressions was measured by real-time PCR (Viia7™,Applied Biosystems). The PCR buffer used was TaqMan Fast Advanced MasterMix (Applied Biosystems), and TaqMan Gene Expression Assays (AppliedBiosystems) Mm00439618_ml (IL-17A) and 4352341E (β-actin) were used foreach gene detection. The IL-17A gene expression level was normalized tothe β-actin gene expression level, and the percent inhibition of IL-17Agene expression with the test compound was then calculated.

The results (percent inhibition of IL-17A gene expression with oraladministration of the test compound) measured by the above-mentionedmethod are shown in Table 9.

TABLE 9 percent inhibition Example Dose of IL-17A gene number mg/kgexpression* 4 10 86% 5 10 57% 6 10 95% 8 10 72% 9 10 57% 10 10 87% 13 1091% 15 3 99% 18 10 72% 19 10 90% 20 10 99% 23 10 96% 24 10 74% 25 10 92%28 10 91% 29 10 73% 31 10 85% 32 10 83% 33 10 94% 36 10 78% *versus thenegative control group

The results above showed that oral administration of the examplecompounds inhibited IL-17A gene expression in vivo.

Experimental Example 6 Effect in an IL-23-Induced Mouse Psoriasis Model

Mouse IL-23 (500 ng/15 μL, R&D) or PBS (15 μL, negative control group)was administered intradermally in the ear of Balb/c mice (Charles RiverJapan, male, 7 weeks old) 5 times every other days. Seven hr after IL-23administration at 8 days after the initial administration (finaladministration), the mice were anesthetized with isoflurane, and earthickness was measured with calipers. After the ear thickness wasmeasured, the ear was resected, tissue 8 mm in diameter was punched froman area centering on the IL-23 injection site, and the tissue wasweighed. The punched ear tissue was cut in half, and one half wasimmersion-fixed in 10% neutral buffer formalin solution for use inhistopathological evaluation. The other half was immersed in RNAlater(QIAGEN) for at least 18 hr for use in an evaluation of the IL-17A mRNAexpression level. The test compound was suspended in 0.5%methylcellulose and administered orally twice daily on consecutive daysfrom 30 min before the initial IL-23 administration to 30 min before thefinal IL-23 administration.

The change in ear thickness in this model was evaluated by calculatingthe difference in measured thickness between before IL-23 administrationand 7 hr after the final IL-23 administration. In addition, theformalin-fixed tissue was embedded and sectioned, then stained withhematoxylin-eosin. The degree of acanthosis was then evaluatedqualitatively by microscopy (classified with a score of 0 to 4). RNAextraction from the ear tissue and quantitative PCR were performed asfollows. As described above, ear tissue treated with RNAlater (QIAGEN)was homogenized in 350 μL of RLT buffer (RNeasy mini kit, QIAGEN) andtreated (55° C., 10 min) with Proteinase K (QIAGEN). Total RNA was thenextracted according to the RNeasy mini kit protocol. The RNA thusobtained was reverse transcribed into cDNA using the High-CapacityRNA-to-cDNA kit (Applied Biosystems), and the expression of each genewas measured by real-time PCR (Viia7™, Applied Biosystems). The PCRbuffer used was TaqMan Fast Advanced Master Mix (Applied Biosystems),and TaqMan Gene Expression Assays (Applied Biosystems) Mm00439618_ml(IL-17A) and 4352341E (β-actin) were used to detect the genes. TheIL-17A gene expression level was normalized to the β-actin geneexpression level, and the percent inhibition of IL-17A gene expressionwith the test compound was then calculated.

The results (percent inhibition of ear thickness, acanthosis score andIL-17A gene expression with oral administration of the test compound)measured by the above-mentioned method are shown in Table 10.

TABLE 10 percent percent percent inhibition Ex. Dose inhibition ofinhibition of of IL-17A No. mg/kg ear thickness* acanthosis score*expression* 6 10 64% 39% 111%  10 1 52% 47% 91% 15 3 61% 53% 93% 19 1040% 29% 94% *versus the negative control group

Experimental Example 7 Effect in a T Cell-Transferred Mouse ColitisModel

Balb/c mice (Charles River Japan, female, 8 weeks old) were euthanized,and the spleens were resected, mashed in mesh, and passed through cellstrainer to prepare a suspension of splenic cells. The mononuclear cellfraction in the splenic cells was isolated by density-gradientcentrifugation, and subjected to hemolysis treatment with ammoniumchloride buffer solution (Immuno-Biological Laboratories, Co., Ltd.).The naive T-cells were purified using CD4+CD62L+ T Cell Isolation Kit II(Miltenyi Biotec). The naive T-cells (2×10⁵ cells/mouse) wereintravenously transferred into SCIDmice (CLEA Japan, female, 8 weeksold). The compound was suspended in 0.5% methyl cellulose, and thesuspension was orally administered twice daily on consecutive days fromthe same evening of the cell transfer. The mice were blinded 20 daysafter the cell transfer, and the symptom of the stool on floorclothunder blind was evaluated by scores of 1 to 4 (1: normal, 2: loosestool, 3: diarrhea (formed), 4: diarrhea (unformed)) 21 days after thecell transfer. The large intestine was resected under isofluraneanesthesia, and the feces were removed. The large intestine was washedwith saline, and the weight was measured.

The results (percent inhibition of intestinal tract weight and diarrheascore with oral administration of the test compound) measured by theabove-mentioned method are shown in Table 11.

TABLE 11 Ex. Dose percent inhibition of percent inhibition of No. mg/kgintestinal tract weight* diarrhea score* 15 3 58% 81% *versus thenegative control group

Experimental Example 8 Effect in a Mouse EAE Model

A solution of MOG₃₅₋₅₅ (2 mg/mL, BEX, synthesized by commissioning) wasmixed in equal amount with FCA (DIFCO) wherein H37Ra (5 mg/mL, DIFCO)was suspended, and the mixture was emulsified using sonicator to give anemulsion. C57BL/6J mice (10 weeks old, female, Charles River Japan) weregrouped based on the body weight, and the MOG emulsion was intradermallyadministered at two point of the joint of dorsal hindlimb so that thedose was 100 μL/site, 200 μL/mouse. In addition, Pertussis toxin (Merck)was intraperitoneally administered twice on the sensitization day and 2days thereafter in the dose of 400 ng/200 μL/mouse. The body weight wasmeasured twice a week before onset and everyday (excluding holiday)after onset from the sensitization day. The clinical score was evaluatedby the following standard scores of 0 to 5 (0: normal, 0.5: partialparalysis of tail, 1: complete paralysis of tail, 2: partial paralysisof hindlimb, 3: paralysis of lower body, 4: partial paralysis offorelimb, 5: paralysis of both forelimbs or death) by observationeveryday (excluding holiday) after the beginning of onset.

The percent inhibition of the clinical score of the test compoundadministration group relative to that of the control group wascalculated using integration value of the clinical score for 28 days.

The results (percent inhibition of clinical score with oraladministration of the test compound) measured by the above-mentionedmethod are shown in Table 12.

TABLE 12 Ex. Dose percent inhibition No. mg/kg of clinical score* 15 364% *versus the negative control group

The results above showed that oral administration of the examplecompounds inhibited the increase in ear thickness, acanthosis, andIL-17A gene expression in the mouse model of psoriasis.

Formulation Example 1

(1) the compound of Example 1 10.0 g (2) lactose 70.0 g (3) cornstarch50.0 g (4) soluble starch  7.0 g (5) magnesium stearate  3.0 g

The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) aregranulated in aqueous solution (70 mL) of soluble starch (7.0 g assoluble starch) and then dried, the resulting mixture is mixed withlactose (70.0 g) and cornstarch (50.0 g) (lactose, cornstarch, solublestarch and magnesium stearate are all products in compliance withJapanese Pharmacopoeia 14^(th) Edition). The mixture compressed to givetablets.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior RORγt inhibitoryaction, and useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

This application is based on patent application Nos. 2014-136359 and2014-262775 filed in Japan, the contents of which are encompassed infull herein.

1-7. (canceled) 8.cis-3-(((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylicacid or a salt thereof. 9-13. (canceled)
 14. A method of inhibitingRORγt in a mammal, which comprises administering an effective amount ofthe compound or salt of claim 8 to the mammal. 15-17. (canceled)